Novel pyrazole derivative

ABSTRACT

It has been desired to develop a pharmaceutical composition, which is used in agents for preventing and/or treating various diseases related to PDE10 (e.g. mental disorder and neurodegenerative disorder). The present invention provides: compounds having PDE10 inhibitory effect, in particular, compounds having a 4-heteroarylpyrazole-5-carboxylic acid amide structure represented by the following formula (I), or their pharmaceutically acceptable salts, or their solvates; pharmaceutical compositions comprising, as active ingredients, the compounds, or their pharmaceutically acceptable salts, or their solvates; and medical use of the compounds, or their pharmaceutically acceptable salts, or their solvates.

TECHNICAL FIELD

The present invention relates to a compound having phosphodiesterase 10(hereinafter referred to as “PDE10”) inhibitory effect, in particular, acompound having a 4-heteroarylpyrazole-5-carboxylic acid amide structurerepresented by the following formula (I), or a pharmaceuticallyacceptable thereof, or a solvate thereof; and a pharmaceuticalcomposition comprising, as an active ingredient, the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof; or anagent for preventing and/or treating various diseases related to PDE10(e.g. mental disorders and neurodegenerative disorders).

BACKGROUND ART

Phosphodiesterase (PDE, cyclic nucleotide phosphodiesterase) is asuperfamily of enzymes encoded by 21 different genes. To date, elevenphosphodiesterases have been identified in mammals, based onstructural/functional characteristics such as amino acid sequencehomology, biochemical properties, and characterization using inhibitors(Non Patent Literatures 1 and 2).

The role of the PDE in cell signaling cascade is to hydrolyze thephosphodiester bond of cyclic nucleotides, adenosine 3′,5′-cyclicmonophosphate (cAMP) and/or guanosine 3′,5′-cyclic monophosphate (cGMP),that is to say, to selectively catalyze the hydrolysis of a 3′-esterbond so as to form inactive 5′-monophosphoric acid so as tometabolically inactivate the cyclic nucleotides.

The eleven PDE families are classified into three groups, namely,cAMP-specific PDEs (PDE 4, 7, and 8), cGMP-specific PDEs (PDE 5, 6, and9), and double substrate PDEs (PDE 1, 2, 3, 10, and 11) (Non PatentLiteratures 3 and 4) based on substrate specificity.

Since cAMP and cGMP are important second messengers in intracellularsignaling via G protein coupled receptors (GPCR), PDEs are involved in awide range of physiological mechanisms and play an important role in thehomeostasis of organisms. Specifically, PDEs are related to variousphysiological processes such as generation of proinflammatory mediatorsand the action thereof, ion channel function, muscle relaxation,learning and memory formation, differentiation, apoptosis, lipogenesis,glycogenolysis, and gluconeogenesis. Particularly, in nerve cells, PDEsplay an important role in the differentiation and survival of nervecells and the regulation of neurotransmission (Non Patent Literature 5).

Regulation of these processes by cAMP and cGMP is related to activationof protein kinase A (PKA) and protein kinase G (PKG), and thus, varioussubstrates that regulate various physiological processes, such astranscriptional factors, ion channels, and receptors, arephosphorylated. The intracellular levels of cAMP and cGMP are fluctuatedin response to extracellular signals, and are regulated based on thebalance between enzymes involved in the synthesis of cAMP and cGMP(adenyl cyclase (AC) and guanyl cyclase (GC)), and PDEs involved in thehydrolysis of these enzymes (Non Patent Literature 6).

The presence of PDE10 in humans, mice, and rats was reported in 1999(Non Patent Literatures 7 and 8). PDE10 is mainly expressed in thebrain, testis, thyroid gland, and the like in humans. In particular,PDE10 is highly expressed in medium-sized spiny neurons (MSNs) in thecorpus striatum of the brain, and is moderately expressed in thethalamus, hippocampus, frontal cortex, and olfactory tubercle (NonPatent Literatures 9 and 10). In addition, PDE10 is highly expressed inthe brain and testis also in mice and rats (Non Patent Literature 11).Since the brain sites where PDE10 is expressed play an important role inthe pathological mechanism of mental diseases, it has been suggestedthat PDE10 is involved in the pathological mechanism of mentaldisorders, neurodegenerative disorders, and the like (Non PatentLiterature 12).

There are two types of MSN, namely, MSN that mainly expresses D1dopamine receptors and forms a nigrostriatal pathway (direct pathway)and MSN that mainly expresses D2 dopamine receptors and forms astriatum-globus pallidus pathway (indirect pathway). The direct pathwayis involved in the functions of motor execution and reward learning, andthe indirect pathway is involved in the suppression of movement. Forexample, deterioration of movements in Parkinson's disease is caused byexcessive action of the indirect pathway, and excessive movementsobserved in disorders such as Huntington's disease are caused byexcessive action of the direct pathway. The activity of the outputnucleus of the basal ganglia is regulated by the balance betweenantagonistic inputs from these two types of pathways. Since PDE10 isexpressed in MSNs in both pathways, both pathways are considered to beactivated by inhibition of PDE10 (Non Patent Literature 13).

The existing antipsychotic agents are mainly D₂ receptor blockingagents, and are mainly mediated by activation of the indirect pathway.On the other hand, PDE10 is expressed in both MSNs in the direct pathwayand the indirect pathway, and thus, a PDE10 inhibitor is expected tohave the same antipsychotic action as that of the existing agents. Sincethe direct pathway is involved in motor execution, the direct pathway isconsidered to antagonistically act against extrapyramidal disordercaused by excessive activation of the indirect pathway. Moreover, it canalso be expected that the direct pathway has action to reinforce theoutput from the corpus striatum-thalamus circuit and to promotecognitive function such as reward learning or problem solving.

As a result of an increase in the intracellular cAMP level by activationof the D₁ receptor, a series of neurites involved in working memory inthe prefrontal cortex are likely to be regulated (Non Patent Literature14). Furthermore, it has been reported that working memory deficits ofschizophrenia patients may be improved by activation of the D₁ receptor(Non Patent Literature 15). Accordingly, it can be anticipated that thecognitive symptoms of schizophrenia will be improved by activation ofthe D₁ receptor.

Potential antipsychotic action of a PDE10 inhibitor has been attested bythe study of Kostowski et al. (Non Patent Literature 16). According toU.S. Patent Application No. 2003/0032579, papaverine a PDE10 inhibitorhaving a moderate selectivity decreases apomorphine-induced stereotypyin rats which is an animal model of psychosis, and increaseshaloperidol-induced catalepsy in rat, and at the same time, papaverinealso decreases the dopamine level in the rat brain and has conventionalaction as an antipsychotic agent. Further, the antipsychotic action ofpapaverine has been also proved by the application thereof to patients,and papaverine has been established as a PDE10 inhibitor for thetreatment of psychosis (Patent Literature 1).

With regard to compounds having PDE10 inhibitory effect (PDE10inhibitors), there are the following reports. For instance,International Publication No. WO2005/082883 (Patent Literature 2) andEuropean Patent Application No. 1250923 (Patent Literature 3) disclose,as PDE10 inhibitors, papaverine (isoquinoline alkaloid contained inPapaver plants) and various types of aromatic heterocyclic compounds(quinazoline and isoquinazoline compounds, etc.). In addition, it hasalso been disclosed that the PDE10 inhibitor is useful for treating orpreventing diseases or symptoms, such as mental disorder (e.g.schizophrenia, schizophreniform disorder, paranoid disorder,substance-induced psychosis, paranoic personality disorder, andschizophrenic personality disorder), anxiety disorder (e.g. panicdisorder, agoraphobia, specific phobias, anthropophobia,obsessive-compulsive disorder, posttraumatic stress disorder, acutestress disorder, and generalized anxiety disorder), motor disorder (e.g.Huntington's disease, dyskinesia associated with dopamine agonisttherapy, Parkinson's disease, and restless legs syndrome), drugdependence (e.g. alcohol, amphetamine, cocaine or opiate addiction),diseases attended with the symptoms of cognitive disorder (e.g. dementia(Alzheimer's disease, multi-infarct dementia, etc.), delirium, amnesticdefect, posttraumatic stress disorder, mental retardation, learningdisorder, attention-deficit hyperactivity disorder (ADHD), andage-related cognitive function reduction), and mood disorder (e.g. majordepressive disorder, dysthymic disorder, minor depressive disorder, andbipolar disorder (bipolar disorder type I and bipolar disorder type II),and cyclothymic disorder), or mood symptoms (e.g. major depressiveepisode, manic or mixed affective episode, and hypomanic episode).Moreover, it has also been disclosed that the PDE10 inhibitor is usefulfor treating or preventing neurodegenerative disease (e.g. Parkinson'sdisease and Huntington's disease).

The publication of Menniti et al. reports that the PDE10 inhibitor has apotential as an antipsychotic agent and also has a potential forimproving cognitive function disorder in schizophrenia (Non PatentLiterature 17).

International Publication No. WO2003/000693 discloses an imidazotriazinecompound as a PDE10 inhibitor, and that the PDE10 inhibitor is usefulfor treating or preventing neurodegenerative diseases (in particular,Parkinson's disease) (Patent Literature 4).

As described above, it is anticipated that the PDE10 inhibitor can be atherapeutic agent with reduced adverse drug reactions, which is usefulfor treating and/or preventing mental disorders related to PDE10 (e.g.(1) paranoid, disorganized, catatonic, undifferentiated, or residualschizophrenia, (2) schizophreniform disorder, (3) paranoid or depressiveschizoaffective disorder, (4) paranoid disorder, (5) substance-inducedmental disorder, for example, psychosis induced by alcohol, amphetamine,cannabis, cocaine, a hallucinatory drug, an inhalant, opioid, orphencyclidine, (6) paranoic personality disorder, and (7) schizotypalpersonality disorder); neurodegenerative disorders related to PDE10(e.g. (1) Parkinson's disease, (2) Huntington's disease, (3) dementia,such as Alzheimer's disease, multi-infarct dementia, AIDS-relateddementia, and frontotemporal dementia, (4) neurodegeneration associatedwith brain damage, (5) neurodegeneration associated with stroke andneurodegeneration associated with cerebral infarction, (6)hypoglycemia-induced neurodegeneration, (7) neurodegeneration associatedwith epileptic seizure, (8) neurodegeneration associated with neurotoxicaddiction, (9) multiple system atrophy, and (10) neurodegeneration ofstriatal medium-sized spiny neurons); and the like.

International Publication No. WO2006/0072828 (Patent Literature 5)discloses, as a PDE10 inhibitors, compounds having a1-methyl-4-heteroarylpyrazole structure as a partial structure thereof.However, this structure is different from the structure of the compoundin the present invention.

International Publication No. WO2011/036127 (Patent Literature 6),International Publication No. WO2011/154327 (Patent Literature 7), andInternational Publication No. WO2012/076430 (Patent Literature 8)disclose compounds having a pyrazole-5-carboxylic acid amide structureas a PDE10 inhibitors. However, the structures of the compounds ofPatent Literatures 6, 7, and 8 are all different from the structure ofthe compound in the present invention in that the compounds of PatentLiteratures 6 and 8 have a dicarboxylic acid amide structure and in thatthe compound of Patent Literature 7 is a carboxylic acid amide of7-aminoimidazo[1,2-a]pyrimidine.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Literature 1: U.S. Patent Application No. 2003/0032579-   Patent Literature 2: International Publication No. WO2005/082883-   Patent Literature 3: European Patent Application No. 1250923-   Patent Literature 4: International Publication No. WO2003/000693-   Patent Literature 5: International Publication No. WO2006/072828-   Patent Literature 6: International Publication No. WO2011/036127-   Patent Literature 7: International Publication No. WO2011/154327-   Patent Literature 8: International Publication No. WO2012/076430

Non-Patent Documents

-   Non Patent Literature 1: Essayan D M., J Allergy Clin Immunol, 108,    p 671-680, 2001.-   Non Patent Literature 2: Francis S H., Prog Nucleic Acid Res Mol    Biol., 65, p 1-52, 2001.-   Non Patent Literature 3: Soderling S H., Proc Natl Acad USA, 96(12),    p 7071-7076, 1999.-   Non Patent Literature 4: Chappie T A., Journal of Medicinal    Chemistry, 55, p 7299-7331, 2012.-   Non Patent Literature 5: Menniti F S., Nat Rev Drug Discov, 5(8), p    660-670, 2006.-   Non Patent Literature 6: Houslay M D., Cir Res, 100(7), p 950-966,    2007.-   Non Patent Literature 7: Omori K., J Biol Chem, 274(26), p    18438-18445, 1999.-   Non Patent Literature 8: Loughney K., Gene, 234(1), p 109-117, 1999.-   Non Patent Literature 9: Omori K., Eur J Biochem, 266(3), p    1118-1127, 1999.-   Non Patent Literature 10: Menniti F S., Brain Res, 985(2), p    113-126, 2003.-   Non Patent Literature 11: Xie Z., Neuroscience., 139(2), p 597-607,    2006.-   Non Patent Literature 12: Lapiz et al., Neurosci Behav Physiol,    33(1), p 13-29, 2003.-   Non Patent Literature 13: Mutschler., Arzneimittelwirkungen. 8^(th)    ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 2001.-   Non Patent Literature 14: Sawaguchi., Parkinsonism Relat Disord.,    7(1), p 9-19, 2000.-   Non Patent Literature 15: Castner S A., Science., 287(5460), p    2020-2022, 2000.-   Non Patent Literature 16: Kostowski W., Pharmacol Biochem Behay.,    5(1), p 15-17, 1976.-   Non Patent Literature 17: Menniti F S., Curr Opin Investig Drugs.,    8(1), p 54-59, 2007.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

At present, various antipsychotic agents can be used in drug therapy forschizophrenia. However, such antipsychotic agents have a low level ofsatisfaction in treatment. Conventional antipsychotic agents having highaffinity for dopamine D₂ receptors, such as haloperidol, exhibit strongadverse effects including extra pyramidal symptom (EPS) and do notimprove the negative symptoms of schizophrenia, thus the agents cannotget patients back to daily life. Clozapine, which had been developed asstandard therapy for improving the positive, negative, and cognitivesymptoms of schizophrenia and which has not exhibited EPS, has beenplaced on the market as a benchmark for treating and recovering thepositive, negative, and cognitive symptoms of schizophrenia. However,this clozapine causes granulocytopenia as a severe potentially lethaladverse drug reaction (Capuano B., Curr Med Chem, 9 (5), pp. 521-548,2002). Moreover, many therapy-resistant cases are still present(Lindenmayer J P., J Clin Psychiatry, 63 (10), pp. 931-935, 2002). Inconclusion, it has been desired to develop a novel antipsychotic agentfor improving the positive, negative, and cognitive symptoms ofpsychosis and having a better adverse effect profile.

Moreover, in the development of pharmaceutical products, it is requiredto satisfy strict criteria, not only in terms of pharmacologicalactivities of interest, but also in terms of various aspects such asabsorption, distribution, metabolism, and excretion. For example,pharmaceutical products are required to overcome various problemsregarding drug interaction, desensitization or tolerance,gastrointestinal absorption upon oral administration, rate oftransferring into the small intestine, absorption rate and first passeffect, organ barriers, protein binding, induction or inhibition of drugmetabolizing enzymes, excretion pathway and inner clearance, applicationmethods (application site, method, and purpose), and the like. It isdifficult to discover a pharmaceutical product that satisfies theserequirements.

There have been several reports regarding a compound having inhibitoryeffect on the PDE10 receptor. However, the above-mentioned generalproblems have always remained unsolved during the development ofpharmaceutical products, and thus, such a compound has not yet beenplaced on the market. More specifically, regarding usefulness andsafety, there are problems such as poor solubility, low metabolicstability and difficult systemic exposure by oral administration, poordrug pharmacokinetics such as absorbability and persistence, that acompound exhibits inhibitory activity on human ether-a-go-go relatedgene (hERG) channel, which may have a risk of causing arrhythmia, that acompound exhibits an activity of inducing or inhibiting drugmetabolizing enzyme (e.g. cytochrome P450), and that a compound exhibitsa high protein-binding rate. It has been desired to discover a compoundthat solves as many of these problems as possible and has higheffectiveness.

Means for Solving the Problems

The present inventors have conducted intensive studies directed towardssolving the aforementioned problems and obtaining a PDE10 inhibitor thatis highly safe and/or is excellent in effectiveness. As a result, theinventors have discovered that a compound having a4-heteroarylpyrazole-5-carboxylic acid amide structure represented by aformula (I), or a pharmaceutically acceptable salt thereof, or a solvatethereof has PDE10 inhibitory effect. The compounds in the presentinvention have PDE10 inhibitory effect and also have effect to improvevarious diseases related to PDE10 (e.g. mental disorder andneurodegenerative disorder).

Effects of the Invention

The present invention is a compound having a4-heteroarylpyrazole-5-carboxylic acid amide structure represented bythe formula (I), or a pharmaceutically acceptable salt thereof, or asolvate thereof; and a pharmaceutical composition comprising, as anactive ingredient, the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

The compound in the present invention is a compound having PDE10inhibitory effect. This compound has action to inhibit the hydrolysis ofa phosphodiester bond of cAMP in striatal GABA neurons and increasenerve ignition by inhibiting PDE10, and to improve various diseasesrelated to PDE10 (e.g. mental disorders and neurodegenerative disorders)by promoting the activation of the corpus striatum.

A pharmaceutical composition comprising, as an active ingredient, thecompound in the present invention can be preferably administered by oraladministration, and it is expected to be an agent for preventing and/ortreating diseases related to PDE10.

Moreover, a group of the compounds of the present invention is highlyuseful because these compounds have at least one characteristic of goodsolubility, high metabolic stability, excellent oral absorbability, andhaving only small action to inhibit the hERG channel.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

The present invention is a compound having a4-heteroarylpyrazole-5-carboxylic acid amide structure represented bythe following formula (I), or a pharmaceutically acceptable saltthereof, or a solvate thereof; a pharmaceutical composition comprising,as an active ingredient, the compound, a pharmaceutically acceptablesalt thereof, or a solvate thereof; and a PDE10 inhibitor as medicinaluse of the compounds, a pharmaceutically acceptable salt thereof, or asolvate thereof, which are described in the following embodiments.

The present invention includes the following embodiments [1] to [17].

A first embodiment of the present invention is

[1] a compound represented by the following formula (I), or apharmaceutically acceptable salt thereof, or a solvate thereof:

wherein p represents an integer of 0 to 4; q represents an integer of 0to 4; Z represents N or CR⁵; R¹ each independently represents a halogenatom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkylgroup, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, aC₁₋₆ alkoxycarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a—CONR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸group each independently represent a substituent selected from among ahydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, ahydroxy C₁₋₆ alkyl group, a cyanated C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₄ arylgroup, a C₇₋₂₀ aralkyl group, a heterocyclic group, a C₂₋₇ alkanoylgroup, a hydroxy C₂₋₇ alkanoyl group, a halogenated C₂₋₇ alkanoyl group,a C₃₋₈ cycloalkylcarbonyl group, a C₆₋₁₄ arylcarbonyl group, a C₇₋₂₀aralkylcarbonyl group, a heterocyclic carbonyl group, a mono-/di-C₁₋₆alkylcarbamoyl group, a mono-/di-halogenated C₁₋₆ alkylcarbamoyl group,a mono-/di-C₃₋₈ cycloalkylcarbamoyl group, a mono-/di-C₆₋₁₄arylcarbamoyl group, a mono-/di-C₇₋₂₀ aralkylcarbamoyl group, amono-/di-heterocyclic carbamoyl group, a C₁₋₆ alkylsulfonyl group, ahalogenated C₁₋₆ alkylsulfonyl group, a C₃₋₈ cycloalkylsulfonyl group, aC₆₋₁₄ arylsulfonyl group, a C₇₋₂₀ aralkylsulfonyl group, a heterocyclicsulfonyl group, a mono-/di-C₁₋₆ alkylsulfamoyl group, amono-/di-halogenated C₁₋₆ alkylsulfamoyl group, a mono-/di-C₃₋₈cycloalkylsulfamoyl group, a mono-/di-C₆₋₁₄ arylsulfamoyl group, amono-/di-C₇₋₂₀ aralkylsulfamoyl group, and a mono-/di-heterocyclicsulfamoyl group; R² represents a hydrogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆alkoxyl C₁₋₆ alkyl group; R³ each independently represents a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group,a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆alkoxyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group; R⁴ represents ahalogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group havethe same definitions as those of R⁷ and R⁸ in the above R¹, a C₆₋₁₄ arylgroup, a 3- to 14-membered non-aromatic heterocyclic group, or a 5- to7-membered monocyclic heteroaryl group, wherein the C₃₋₈ cycloalkylgroup, the C₆₋₁₄ aryl group, the 3- to 14-membered non-aromaticheterocyclic group, and the 5- to 7-membered monocyclic heteroarylgroup, which are represented by R⁴, are optionally substituted with oneto three groups selected from among a hydroxyl group, a nitro group, acyano group, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group havethe same definitions as those of R⁷ and R⁸ in the above R¹, a C₆₋₁₄ arylgroup, a 3- to 14-membered non-aromatic heterocyclic group, and a 5- to7-membered monocyclic heteroaryl group; R⁵ represents a hydrogen atom, ahalogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₁₋₆alkoxyl group, a halogenated C₁₋₆ alkoxyl group, or a C₁₋₆ alkoxyl C₁₋₆alkyl group;

ring A represented by the following partial structural formula (II):

represents a 5- to 7-membered monocyclic heteroaryl group which has astructure in which position 4 of a pyrazole ring directly binds toposition a to a nitrogen atom of the 5- to 7-membered monocyclicheteroaryl group, and is selected from the group of the heteroarylsconsisting of the following:

R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, or a hydroxy C₁₋₆ alkyl group; and

fused ring B represented by the following partial structural formula(III):

is selected from the group consisting of the following:

Hereinafter, individual groups in the above formula (I) of theembodiment [1] will be specifically described.

In explanation regarding the compound in the present invention, forexample, the term “C₁₋₆” indicates that the number of constituent carbonatoms is 1 to 6, and it indicates the number of carbon atoms in astraight-chain, branched-chain, or cyclic group, unless otherwisespecified. The number of constituent carbon atoms includes the totalnumber of carbon atoms of groups including straight-chain orbranched-chain groups substituted with cyclic groups, or cyclic groupssubstituted with straight-chain or branched-chain groups. Accordingly,the chain group means a “straight chain or branched chain, the number ofconstituent carbon atoms of which is 1 to 6.” On the other hand, thecyclic group means a “cyclic group in which the number of carbon atomsthat constitute a ring is 1 to 6.” A group comprising a chain group anda cyclic group means a “group, the total number of carbon atoms of whichis 1 to 6.”

In the present specification, unless otherwise specified, examples ofthe “halogen atom” include a fluorine atom, a chlorine atom, a bromineatom, and an iodine atom.

In the present specification, unless otherwise specified, the term“halogenated” means that a group optionally has one to five of the abovedescribed “halogen atoms” as substituents. In addition, the term“halogenated” can be restated as “optionally halogenated” or “halogeno.”

In the present specification, unless otherwise specified, the term“cyanated” means that a group optionally has one to five of the abovedescribed “cyano groups” as substituents. In addition, the term“cyanated” can be restated as “optionally cyanated.”

In the present specification, unless otherwise specified, examples ofthe “alkyl group” include a “C₁₋₆ alkyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkyl group” include methylethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl,isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,2-cyclobutylethyl, and 2-methylcyclopropyl.

In the present specification, unless otherwise specified, the term“halogenated C₁₋₆ alkyl group” means a group in which the abovedescribed “C₁₋₆ alkyl group” is optionally substituted with one to fivehalogen atoms. Examples of the halogenated C₁₋₆ alkyl group includefluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, and pentafluoroethyl.

In the present specification, unless otherwise specified, the term“hydroxy C₁₋₆ alkyl group” means a group in which the above described“C₁₋₆ alkyl group” is optionally substituted with one to five hydroxylgroups. Examples of the hydroxy C₁₋₆ alkyl group include hydroxymethyl,hydroxyethyl (specifically, 1-hydroxyethyl and 2-hydroxyethyl),hydroxypropyl (specifically, 1-hydroxypropyl, 2-hydroxypropyl,3-hydroxypropyl, etc.), and 2-hydroxy-2-methyl-ethyl.

In the present specification, unless otherwise specified, the term“cyanated C₁₋₆ alkyl group” means a group in which the above described“C₁₋₆ alkyl group” is optionally substituted with one to five cyanogroups. Examples of the cyanated C₁₋₆ alkyl group include cyanomethyl,1-cyanoethyl, and 2-cyanoethyl.

In the present specification, unless otherwise specified, examples ofthe “alkenyl group” include a “C₂₋₆ alkenyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₂₋₆ alkenyl group” include vinyl, allyl, isopropenyl,1-propen-1-yl, 2-methylallyl, butenyl, pentenyl, isopentenyl, hexenyl,1-cyclopropen-1-yl, 2-cyclopropen-1-yl, 1-cyclobuten-1-yl,1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,2,4-cyclopentadien-1-yl, and 2,5-cyclohexadien-1-yl.

In the present specification, unless otherwise specified, examples ofthe “alkynyl group” include a “C₂₋₆ alkynyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₂₋₆ alkynyl group” include ethynyl, 1-propynyl, 2-propynyl,butynyl, pentynyl, and hexynyl.

In the present specification, unless otherwise specified, examples ofthe “aryl group” include a “C₆₋₁₄ aryl group.”

In the present specification, unless otherwise specified, the “C₆₋₁₄aryl group” includes a “monocyclic aryl group,” a “fused-ring aryl group(including bicyclic or tricyclic groups),” and a “partially hydrogenatedfused-ring aryl group (including bicyclic or tricyclic groups).”

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 2-, 3-,or 4-biphenylanthryl, phenanthryl, and acenaphthyl.

In the present specification, unless otherwise specified, the term“partially hydrogenated fused-ring aryl group” means a monovalent groupformed by removing any given hydrogen atom from a partially hydrogenatedfused ring in the above described “fused-ring aryl group.” Either ahydrogen atom in the aromatic ring portion of the fused ring or ahydrogen atom in the hydrogenated portion thereof may be removed.

In the present specification, unless otherwise specified, examples ofthe “partially hydrogenated fused-ring aryl group” include indanyl,indenyl, and 1,2,3,4-tetrahydronaphthyl.

The “aryl group” may be restated as an “aromatic hydrocarbon group.”That is to say, the “C₆₋₁₄ aryl group” means the same group as a “C₆₋₁₄aromatic hydrocarbon group.”

In the present specification, unless otherwise specified, the term“aralkyl group” means a group in which the above described “aryl group”is substituted with the above described “alkyl group.”

In the present specification, unless otherwise specified, examples ofthe “aralkyl group” include a “C₇₋₂₀ aralkyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₇₋₂₀ aralkyl group” include benzyl, phenethyl, diphenylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl,1-indanylmethyl, 2-indanylmethyl,1,2,3,4-tetrahydronaphthalen-1-ylmethyl, and1,2,3,4-tetrahydronaphthalen-2-ylmethyl.

In the present specification, unless otherwise specified, examples ofthe “non-aromatic hydrocarbon group” include a non-aromatic hydrocarbonring containing three to eight carbon atoms, such as a “C₃₋₈ cycloalkylgroup.”

In the present specification, unless otherwise specified, examples ofthe “C₃₋₈ cycloalkyl group” include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, unless otherwise specified, the term“heterocyclic group” means a monovalent group formed by removing anygiven hydrogen atom from a 3- to 14-membered monocyclic or fused ringcontaining one to five heteroatoms that are of at least one optionallyselected from among a nitrogen atom, a sulfur atom, and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe “heterocyclic group” include a “heteroaryl group,” a “partiallyhydrogenated fused-ring heteroaryl group,” and a “non-aromaticheterocyclic group.”

In the present specification, unless otherwise specified, the term“heterocyclic group” can be restated as a “hetero ring group,” the term“heteroaryl group” can be restated as an “aromatic heterocyclic group,”and the term “non-aromatic heterocyclic group” can be restated as a“non-aromatic hetero ring group.”

In the present specification, unless otherwise specified, the abovedescribed “heteroaryl group” means a 5- to 14-membered heteroaryl ringgroup having one to five heteroatoms selected from among a nitrogenatom, a sulfur atom, and an oxygen atom.

In the present specification, unless otherwise specified, examples ofthe above described “heteroaryl group” include a “monocyclic heteroarylgroup” and a “fused-ring heteroaryl group.”

In the present specification, unless otherwise specified, the abovedescribed “monocyclic heteroaryl group” is preferably a group havingfive to seven ring members. That is to say, examples of the “5- to7-membered monocyclic heteroaryl group” include pyrrolyl, furyl,thienyl, thiazolyl, oxazolyl, 1H-imidazolyl, isothiazolyl, isoxazolyl,1H-pyrazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1H-1,2,4-triazolyl,1,2,5-thiadiazolyl, 1,2,5-oxadiazolyl(furazanyl), 2H-1,2,3-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1H-1,2,4-triazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1H-1,2,3-triazolyl,1,2,3,4-thiatriazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-thiatriazolyl,1,2,3,5-oxatriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1,2,3,4-tetrazinyl,1,2,3,5-tetrazinyl, 2H-1,2,3-thiadiazinyl, 4H-1,2,4-thiadiazinyl,6H-1,3,4-thiadiazinyl, 1,4-diazepinyl, and 1,4-oxazepinyl.

In the present specification, unless otherwise specified, the abovedescribed “fused-ring heteroaryl group” means a monovalent group formedby removing any given hydrogen atom from a fused ring that is formed bycondensation of a “heterocyclic group” and an “aryl group,” or of a“heterocyclic group” and a “monocyclic heteroaryl group.” The any givenhydrogen atom may be removed from any of the fused rings.

In the present specification, unless otherwise specified, the abovedescribed “fused-ring heteroaryl group” is preferably a group having 8to 12 ring members. That is to say, examples of the “8- to 12-memberedfused-ring heteroaryl group” include indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl,1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl,2,1,3-benzothiadiazinyl, chromenyl, isochromenyl, 4H-1,4-benzoxazinyl,4H-1,4-benzothiazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, benzoxazepinyl, benzazepinyl,benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl,carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, thieno[3,2-c]pyridyl,thiazolo[5,4-c]pyridyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl,1H-pyrazolo[3,4-b]pyridyl, and 1,2,4-triazolo[1,5-a]pyrimidinyl.

In the present specification, unless otherwise specified, the term“partially hydrogenated fused-ring heteroaryl group” means a monovalentgroup formed by removing any given hydrogen atom from a partiallyhydrogenated fused ring in a fused ring that is formed by condensationof a “heterocyclic group” and an “aryl group,” or of a “heterocyclicgroup” and a “heteroaryl group.” As the any given hydrogen atom, eithera hydrogen atom in any ring portions of the “heterocyclic group,” the“aryl group,” and the “heteroaryl group” in the fused ring, or ahydrogen atom in the hydrogenated ring portion, may be removed. Forexample, if quinoline is partially hydrogenated tetrahydroquinolyl,examples of the partially hydrogenated fused-ring heteroaryl groupinclude 5,6,7,8-tetrahydroquinolyl and 1,2,3,4-tetrahydroquinolyl.Depending on the position from which any given hydrogen atom is removed,examples of the 5,6,7,8-tetrahydroquinolyl include groups with suffixes-2-yl, -3-yl, -4-yl, -5-yl, -6-yl, -7-yl, and -8-yl, and examples of the1,2,3,4-tetrahydroquinolyl include groups with suffixes -1-yl, -2-yl,-3-yl, -4-yl, -5-yl, -6-yl, -7-yl, and -8-yl.

In the present specification, unless otherwise specified, the “partiallyhydrogenated fused-ring heteroaryl group” is preferably a group having 8to 12 ring members. That is to say, examples of the “partiallyhydrogenated 8- to 12-membered fused-ring heteroaryl group” includeindolinyl, 4,5,6,7-tetrahydro-1H-indonyl, 2,3-dihydrobenzofuranyl,4,5,6,7-tetrahydro-benzofuranyl, 2,3-dihydrobenzo[d]oxazolyl,2,3-dihydrobenzo[d]thiazolyl, chromanyl, 2H-chromenyl, 4H-chromenyl,isochromanyl, 1H-isochromenyl, 3,4-dihydro-2H-1,4-benzoxazinyl,3,4-dihydro-2H-1,4-benzothiazinyl, 5,6,7,8-tetrahydroquinolyl,1,2,3,4-tetrahydroquinolyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydroquinazolyl, 1,2-dihydroquinazolyl,2,4-dihydro-1H-benzo[d][1,3]oxazinyl,2,4-dihydro-1H-benzo[d][1,3]thiazinyl, 5,6,7,8-tetrahydroisoquinolyl,1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl,1,2-dihydroquinoxalinyl, 1,4-dihydroquinoxalinyl,1,2,3,4-tetrahydroquinoxalinyl, 4H-benzo[d][1,3]dioxanyl,2,3-dihydrobenzo[b][1,4]dioxanyl, 1,3-benzodioxolyl,2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl,2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,2,3,4,5-tetrahydro-1H-benzo[b]oxepinyl,2,3,4,5-tetrahydro-1H-benzo[b]thiepinyl, and6,7,8,9-tetrahydro-5H-cyclohept[b]pyridyl.

In the present specification, unless otherwise specified, the term“non-aromatic heterocyclic group” means a “3- to 14-membered saturatedor unsaturated non-aromatic heterocyclic group.”

In the present specification, unless otherwise specified, the term “3-to 14-membered saturated or unsaturated non-aromatic heterocyclic group”means a monovalent group formed by removing any given hydrogen atom froma 3- to 14-membered saturated or unsaturated heterocyclic ringcontaining one to four heteroatoms selected from among an oxygen atom, asulfur atom, and a nitrogen atom.

In the present specification, unless otherwise specified, examples ofthe “3- to 14-membered non-aromatic heterocyclic group” includeaziridinyl, azetidinyl, oxiranyl, thiiranyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, pyrazolinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, dihydropyranyl,tetrahydropyranyl(oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl,oxazolidinyl, isoxazolynyl, 1,3-oxazolidinyl, isoxazolidinyl,thiazolinyl, isothiazolinyl, 1,3-thiazolidinyl, isothiazolidinyl,oxadiazolinyl, 1,3,4-oxadiazolidinyl, morpholinyl, thiomorpholinyl,quinuclidinyl, azepanyl, diazepinyl, and oxepanyl.

In the present specification, unless otherwise specified, the term“alkoxyl group” means a group in which the above described “alkyl group”is substituted with an oxygen atom, and examples of the alkoxyl groupinclude a “C₁₋₆ alkoxyl group.” The alkoxyl group is generallyrepresented by RO— (R=alkyl group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy,1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy,1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy,1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 2,2-dimethylbutyloxy,1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutoxy,1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropyloxy,1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy,1-ethyl-2-methylpropyloxy, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy,2-cyclobutylethoxy, and 2-methylcyclopropyloxy.

In the present specification, unless otherwise specified, the term“aryloxy group” means a group in which the above described “aryl group”is substituted with an oxygen atom, and examples of the aryloxy groupinclude a “C₆₋₁₄ aryloxy group.”

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy,2-anthryloxy, and phenanthryloxy.

In the present specification, unless otherwise specified, the term“aralkyloxy group” means a group in which the above described “aralkylgroup” is substituted with an oxygen atom, and examples of thearalkyloxy group include a “C₂₋₂₀ aralkyloxy group.”

In the present specification, unless otherwise specified, examples ofthe “C₂₋₂₀ aralkyloxy group” include benzyloxy, phenethyloxy,3-phenylpropoxy, 1-naphthylmethoxy, 2-naphthylmethoxy,2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy, 1-indanylmethoxy,2-indanylmethoxy, 1,2,3,4-tetrahydronaphthalen-1-ylmethoxy, and1,2,3,4-tetrahydronaphthalen-2-ylmethoxy.

In the present specification, unless otherwise specified, the term “C₁₋₆alkoxyl C₁₋₆ alkyl group” means a group in which the above described“C₁₋₆ alkoxyl group” is substituted with the above described “C₁₋₆ alkylgroup.” In the present specification, unless otherwise specified,examples of the “C₁₋₆ alkoxyl C₁₋₆ alkyl group” include methoxymethyl,methoxyethyl, ethoxymethyl, ethoxyethyl, 1,1-dimethoxymethyl, and1,1-diethoxyethyl.

In the present specification, unless otherwise specified, the term “C₁₋₆alkoxyl C₂₋₆ alkenyl group” means a group in which the above described“C₁₋₆ alkoxyl group” is substituted with the above described “C₂₋₆alkenyl group.” In the present specification, unless otherwisespecified, examples of the “C₁₋₆ alkoxyl C₂₋₆ alkenyl group” include2-methoxyvinyl, 2-ethoxyvinyl, 2-propoxyvinyl, 3-methoxyallyl,3-ethoxyallyl, and 3-ethoxyallyl.

In the present specification, unless otherwise specified, the term“halogenated C₁₋₆ alkoxyl group” means a group in which a “C₁₋₆ alkylgroup” portion of the above described “C₁₋₆ alkoxyl group” is optionallysubstituted with one to five halogen atoms. Examples of the halogenatedC₁₋₆ alkoxyl group include fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, andpentafluoroethoxy.

In the present specification, unless otherwise specified, the term“alkanoyl group” means an “alkylcarbonyl group” in which a carbonylgroup binds to the above described “alkyl group.” Examples of thealkanoyl group include a “C₂₋₇ alkanoyl group.” The alkanoyl group isgenerally represented by R—CO— (R=alkyl group).

In the present specification, unless otherwise specified, examples ofthe “C₂₋₇ alkanoyl group” include acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cyclopropylmethylcarbonyl, and2-methylcyclopropylcarbonyl.

In the present specification, unless otherwise specified, the term“halogenated C₂₋₇ alkanoyl group” means a group in which a “C₁₋₆ alkylgroup” portion of the above described “C₂₋₇ alkanoyl group” isoptionally substituted with one to five halogen atoms. Examples of thehalogenated C₂₋₇ alkanoyl group include trifluoroacetyl and3,3,3-trifluoropropionyl.

In the present specification, unless otherwise specified, the term“hydroxy C₂₋₇ alkanoyl group” means a group in which the above described“C₂₋₇ alkanoyl group” is optionally substituted with one to fivehydroxyl groups. Examples of the hydroxy C₂₋₇ alkanoyl group includehydroxyacetyl and 3-hydroxypropionyl.

In the present specification, unless otherwise specified, the term “C₃₋₈cycloalkylcarbonyl group” means a group in which a carbonyl group bindsto the above described “C₃₋₈ cycloalkyl group.” Examples of the C₃₋₈cycloalkylcarbonyl group include cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,cycloheptylcarbonyl, and cyclooctylcarbonyl.

In the present specification, unless otherwise specified, the term“alkylthio group” means a group in which a hydrogen atom of a “thiolgroup (—SH)” is substituted with the above described “alkyl group.”Examples of the alkylthio group include a “C₁₋₆ alkylthio group.” Thealkylthio group is generally represented by —SR (R=alkyl group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylthio group” include methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,pentylthio, isopentylthio, neopentylthio, tert-pentylthio,1-methylbutylthio, 2-methylbutylthio, 1,2-dimethylpropylthio,1-ethylpropylthio, hexylthio, isohexylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 2,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio,2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio,1-ethyl-1-methylpropylthio, and 1-ethyl-2-methylpropylthio. In addition,the “alkylthio group” can be restated as an “alkylsulfanyl group.” Thatis to say, the “C₁₋₆ alkylthio group” means the same group as a “C₁₋₆alkylsulfanyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₃₋₈ cycloalkylthio group” include cyclopropylthio, cyclobutylthio,cyclopentylthio, and cyclohexylthio.

In the present specification, unless otherwise specified, the term“alkylsulfinyl group” means a group in which a “sulfinyl group (—S(O)—)”is substituted with the above described “alkyl group.” Examples of thealkylsulfinyl group include a “C₁₋₆ alkylsulfinyl group.” Thealkylsulfinyl group is generally represented by —S(O)R (R=alkyl group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfinyl group” include methylsulfinyl, ethylsulfinyl,propylsulfinyl, and isopropylsulfinyl.

In the present specification, unless otherwise specified, the term“alkylsulfonyl group” means a group in which a “sulfonyl group (—SO₂—)”is substituted with the above described “alkyl group.” Examples of thealkylsulfonyl group include a “C₁₋₆ alkylsulfonyl group.” Thealkylsulfonyl group is generally represented by —SO₂R (R=alkyl group).

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl,propylsulfonyl, and isopropylsulfonyl.

In the present specification, unless otherwise specified, the term “C₃₋₈cycloalkylsulfonyl group” means a group in which a “sulfonyl group(—SO₂—)” is substituted with the above described “C₃₋₈ cycloalkylgroup.” Examples of the C₃₋₈ cycloalkylsulfonyl group includecyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl,cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl.

In the present specification, unless otherwise specified, the term“halogenated C₁₋₆ alkylsulfonyl group” means a group in which an “alkylgroup” portion of the above described “C₁₋₆ alkylsulfonyl group” isoptionally substituted with one to five halogen atoms. Examples of thehalogenated C₁₋₆ alkylsulfonyl group include trifluoromethanesulfonyl.

In the present specification, unless otherwise specified, the term“arylsulfonyl group” means a group in which a “sulfonyl group (—SO₂—)”is substituted with the above described “aryl group.” Examples of thearylsulfonyl group include a “C₆₋₁₄ arylsulfonyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ arylsulfonyl group” include phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl, indan-4-sulfonyl,indene-4-sulfonyl, and 5,6,7,8-tetrahydronaphthyl-1-sulfonyl.

In the present specification, unless otherwise specified, the term“aralkylsulfonyl group” means a group in which a “sulfonyl group(—SO₂—)” is substituted with the above described “aralkyl group.”Examples of the aralkylsulfonyl group include a “C₇₋₂₀ aralkylsulfonylgroup.”

In the present specification, unless otherwise specified, examples ofthe “C₇₋₂₀ aralkylsulfonyl group” include benzylsulfonyl andphenethylsulfonyl.

In the present specification, unless otherwise specified, the term“heterocyclic sulfonyl group” means a group in which the above described“heterocyclic group” is substituted with a “sulfonyl group (—SO₂—).”Examples of a “heterocyclic ring” portion of the “heterocyclic sulfonylgroup” include a “heteroaryl group,” a “partially hydrogenatedfused-ring heteroaryl group,” and a “non-aromatic heterocyclic group,”which are exemplified in the above described “heterocyclic group.”

In the present specification, unless otherwise specified, examples ofthe “heterocyclic sulfonyl group” include a “heteroarylsulfonyl group,”a “partially hydrogenated fused-ring heteroarylsulfonyl group,” and a“non-aromatic heterocyclic sulfonyl group.”

In the present specification, unless otherwise specified, examples ofthe “heteroarylsulfonyl group” include pyridylsulfonyl, furanylsulfonyl,and indonylsulfonyl.

In the present specification, unless otherwise specified, examples ofthe “partially hydrogenated fused-ring heteroarylsulfonyl group” includeindolinylsulfonyl, chromanylsulfonyl,5,6,7,8-tetrahydroquinolylsulfonyl,1,2,3,4-tetrahydroquinolyloxycarbonyloxy,1,2,3,4-tetrahydroisoquinolylsulfonyl, and2,3-dihydrobenzo[b][1,4]dioxanylsulfonyl.

In the present specification, unless otherwise specified, examples ofthe “non-aromatic heterocyclic sulfonyl group” includepyrrolidinylsulfonyl, piperidinylsulfonyl, piperazinylsulfonyl, andmorpholinylsulfonyl.

In the present specification, unless otherwise specified, the term “C₁₋₆alkoxylcarbonyl group” means a group in which a hydrogen atom of a“carboxy group (—COOH)” is substituted with the above described “C₁₋₆alkyl group,” namely, it means an “ester group.” The C₁₋₆alkoxylcarbonyl group is generally represented by “the group: —COOC₁₋₆alkyl.”

In the present specification, unless otherwise specified, examples ofthe “C₁₋₆ alkoxylcarbonyl group” include methyl ester (methoxycarbonyl),ethyl ester (ethoxycarbonyl), and tert-butyl ester(tert-butoxycarbonyl).

In the present specification, unless otherwise specified, the term“arylcarbonyl group” means a group in which a carbonyl group binds tothe above described “aryl group.” Examples of the arylcarbonyl groupinclude a “C₆₋₁₄ arylcarbonyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₆₋₁₄ arylcarbonyl group” include benzoyl, 1-naphthoyl(1-naphthylcarbonyl), 2-naphthoyl (2-naphthylcarbonyl),indan-4-carbonyl, indene-4-carbonyl, and5,6,7,8-tetrahydronaphthyl-1-carbonyl.

In the present specification, unless otherwise specified, the term“aralkylcarbonyl group” means a group in which a carbonyl group binds tothe above described “aralkyl group.” Examples of the aralkylcarbonylgroup include a “C₇₋₂₀ aralkylcarbonyl group.”

In the present specification, unless otherwise specified, examples ofthe “C₇₋₂₀ aralkylcarbonyl group” include phenylacetyl and3-phenylpropionyl.

In the present specification, unless otherwise specified, the term“heterocyclic carbonyl group” means a group in which a carbonyl groupbinds to the above described “heterocyclic group.” Examples of a“heterocyclic ring” portion of the “heterocyclic carbonyl group” includea “heteroaryl group,” a “partially hydrogenated fused-ring heteroarylgroup,” and a “non-aromatic heterocyclic group,” which are exemplifiedin the above described “heterocyclic group.”

In the present specification, unless otherwise specified, examples ofthe “heterocyclic carbonyl group” include a “heteroarylcarbonyl group,”a “partially hydrogenated fused-ring heteroarylcarbonyl group,” and a“non-aromatic heterocyclic carbonyl group.”

In the present specification, unless otherwise specified, examples ofthe “heteroarylcarbonyl group,” in which the “heteroaryl group” portionis a “monocyclic heteroaryl group,” include pyrrolylcarbonyl,furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl,oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl,isothiazolylcarbonyl, 1,2,3-triazolylcarbonyl, 1,2,4-triazolylcarbonyl,1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl,1,3,4-oxadiazolylcarbonyl, furazanylcarbonyl,1,2,3-thiadiazolylcarbonyl, 1,2,4-thiadiazolylcarbonyl,1,3,4-thiadiazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl,pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl,1,2,3-triazinylcarbonyl, 1,2,4-triazinylcarbonyl,1,3,5-triazinylcarbonyl, 2H-1,2,3-thiadiazinylcarbonyl,4H-1,2,4-thiadiazinylcarbonyl, 6H-1,3,4-thiadiazinylcarbonyl,1,4-diazepinylcarbonyl, and 1,4-oxazepinylcarbonyl.

Moreover, examples of the “heteroarylcarbonyl group,” in which the“heteroaryl group” portion is a “fused-ring heteroaryl group,” includeindolylcarbonyl, isoindolylcarbonyl, benzofuranylcarbonyl,isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl,benzoxazolylcarbonyl, 1,2-benzisoxazolylcarbonyl,benzothiazolylcarbonyl, 1,2-benzisothiazolylcarbonyl,1H-benzimidazolylcarbonyl, 1H-indazolylcarbonyl,1H-benzotriazolylcarbonyl, 2,1,3-benzothiadiazinylcarbonyl,quinolylcarbonyl, isoquinolylcarbonyl, cinnolinylcarbonyl,quinazolinylcarbonyl, quinoxalinylcarbonyl, phthalazinylcarbonyl,benzoxazepinylcarbonyl, benzazepinylcarbonyl, benzodiazepinylcarbonyl,naphthyridinylcarbonyl, purinylcarbonyl, pteridinylcarbonyl,carbazolylcarbonyl, carbolinylcarbonyl, acridinylcarbonyl,phenoxazinylcarbonyl, phenothiazinylcarbonyl, phenazinylcarbonyl,phenoxathiinylcarbonyl, thianthrenylcarbonyl, phenanthridinyl carbonyl,phenanthrolinyl carbonyl, indolizinylcarbonyl,thieno[3,2-c]pyridylcarbonyl, thiazolo[5,4-c]pyridylcarbonyl,pyrrolo[1,2-b]pyridazinylcarbonyl, pyrazolo[1,5-a]pyridylcarbonyl,imidazo[1,2-a]pyridylcarbonyl, imidazo[1,5-a]pyridylcarbonyl,imidazo[1,2-b]pyridazinylcarbonyl, imidazo[1,5-a]pyrimidinylcarbonyl,1,2,4-triazolo[4,3-a]pyridylcarbonyl,1,2,4-triazolo[4,3-b]pyridazinylcarbonyl,1H-pyrazolo[3,4-b]pyridylcarbonyl, and1,2,4-triazolo[1,5-a]pyrimidinylcarbonyl.

In the present specification, unless otherwise specified, examples ofthe “partially hydrogenated fused-ring heteroarylcarbonyl group” includeindolinylcarbonyl, 4,5,6,7-tetrahydro-1H-indonylcarbonyl,2,3-dihydrobenzofuranylcarbonyl,4,5,6,7-tetrahydro-benzofuranylcarbonyl,2,3-dihydrobenzo[d]oxazolylcarbonyl,2,3-dihydrobenzo[d]thiazolylcarbonyl, chromanylcarbonyl,2H-chromenylcarbonyl, 4H-chromenylcarbonyl, isochromanylcarbonyl,1H-isochromenylcarbonyl, 3,4-dihydro-2H-1,4-benzoxazinylcarbonyl,3,4-dihydro-2H-1,4-benzothiazinylcarbonyl,5,6,7,8-tetrahydroquinolylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl,1,2-dihydroquinolylcarbonyl, 1,2,3,4-tetrahydroquinazolylcarbonyl,1,2-dihydroquinazolylcarbonyl,2,4-dihydro-1H-benzo[d][1,3]oxazinylcarbonyl,2,4-dihydro-1H-benzo[d][1,3]thiazinylcarbonyl,5,6,7,8-tetrahydroisoquinolylcarbonyl, 1,2-dihydroisoquinolylcarbonyl,1,2,3,4-tetrahydroisoquinolylcarbonyl, 1,2-dihydroquinoxalinylcarbonyl,1,4-dihydroquinoxalinylcarbonyl, 1,2,3,4-tetrahydroquinoxalinylcarbonyl,4H-benzo[d][1,3]dioxanylcarbonyl,2,3-dihydrobenzo[b][1,4]dioxanylcarbonyl, 1,3-benzodioxolylcarbonyl,2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinylcarbonyl,2,3,4,5-tetrahydro-1H-benzo[b]azepinylcarbonyl,2,3,4,5-tetrahydro-1H-benzo[b]oxepinylcarbonyl,2,3,4,5-tetrahydro-1H-benzo[b]thiepinylcarbonyl, and6,7,8,9-tetrahydro-5H-cyclohept[b]pyridylcarbonyl.

In the present specification, unless otherwise specified, examples ofthe “non-aromatic heterocyclic carbonyl group” includeaziridinylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl,tetrahydrofurylcarbonyl, piperidinylcarbonyl, tetrahydropyranylcarbonyl,piperazinylcarbonyl, and morpholinylcarbonyl.

In the present specification, unless otherwise specified, the term“amino group” means a substituent wherein, in the “—NR⁷R⁸ group,” R⁷ andR⁸ are each a hydrogen atom.

In the present specification, unless otherwise specified, the term“mono-/di-alkylcarbamoyl group” means a carbamoyl group in which one ortwo hydrogen atoms on a nitrogen atom of the above described “carbamoylgroup” (or R⁷ and R⁸ in “the group: —CONR⁷R⁸”) are substituted with theabove described “alkyl groups.” Examples of the mono-/di-alkylcarbamoylgroup include a “mono-/di-C₁₋₆ alkylcarbamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-C₁₋₆ alkylcarbamoyl group” include methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,isobutylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl, hexylcarbamoyl,isohexylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl,dipentylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl,ethylpropylcarbamoyl, butylmethylcarbamoyl, butylethylcarbamoyl, andbutylpropylcarbamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-cycloalkylcarbamoyl group” means a carbamoyl group in whichone or two hydrogen atoms on a nitrogen atom of the above described“carbamoyl group” (or R⁷ and R⁸ in “the group: —CONR⁷R⁸”) aresubstituted with the above described “cycloalkyl groups.” Examples ofthe mono-/di-cycloalkylcarbamoyl group include a “mono-/di-C₃₋₈cycloalkylcarbamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-C₃₋₈ cycloalkylcarbamoyl group” includecyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, andcyclohexylcarbamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-halogenated C₁₋₆ alkylcarbamoyl group” means a substituent inwhich a “C₁₋₆ alkyl group” portion of the above described “mono-/di-C₁₋₆alkylcarbamoyl group” is optionally substituted with one to five halogenatoms. Examples of the mono-/di-halogenated C₁₋₆ alkylcarbamoyl groupinclude trifluoromethylcarbamoyl, 1,1,1-trifluoroethylcarbamoyl, andditrifluoromethylcarbamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-arylcarbamoyl group” means a carbamoyl group in which one ortwo hydrogen atoms on a nitrogen atom of the above described “carbamoylgroup” (or R⁷ and R⁸ in “the group: —CONR⁷R⁸”) are substituted with theabove described “aryl groups.” Examples of the mono-/di-arylcarbamoylgroup include a “mono-/di-C₆₋₁₄ arylcarbamoyl group.”

In the present specification, unless otherwise specified, specificexamples of the “mono-/di-C₆₋₁₄ arylcarbamoyl group” includephenylcarbamoyl, 2-naphthylcarbamoyl, diphenylcarbamoyl, and2-naphthylphenylcarbamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-aralkylcarbamoyl group” means a carbamoyl group in which oneor two hydrogen atoms on a nitrogen atom of the above described“carbamoyl group” (or R⁷ and R⁸ in “the group: —CONR⁷R⁸”) aresubstituted with the above described “aralkyl groups.” Examples of themono-/di-aralkylcarbamoyl group include a “mono-/di-C₇₋₂₀aralkylcarbamoyl group.”

In the present specification, unless otherwise specified, specificexamples of the “mono-/di-C₇₋₂₀ aralkylcarbamoyl group” includebenzylcarbamoyl and dibenzylcarbamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-heterocyclic carbamoyl group” means a carbamoyl group in whichone or two hydrogen atoms on a nitrogen atom of the above described“carbamoyl group” (or R⁷ and R⁸ in “the group: —CONR⁷R⁸”) aresubstituted with the above described “heterocyclic groups.” Examples ofa “heterocyclic ring” portion of the “mono-/di-heterocyclic carbamoylgroup” include a “heteroaryl group,” a “partially hydrogenatedfused-ring heteroaryl group,” and a “non-aromatic heterocyclic group,”which are exemplified in the above described “heterocyclic group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-heterocyclic carbamoyl group” include a“mono-/di-heteroarylcarbamoyl group,” a “mono-/di-partially hydrogenatedfused-ring heteroarylcarbamoyl group,” and a “mono-/di-non-aromaticheterocyclic carbamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-heteroarylcarbamoyl group,” the “mono-/di-partiallyhydrogenated fused-ring heteroarylcarbamoyl group,” and the“mono-/di-non-aromatic heterocyclic carbamoyl group” includepyridylcarbamoyl, indolylcarbamoyl, tetrahydropyranylcarbamoyl,dipyridylcarbamoyl, benzofuranylpyridylcarbamoyl,furanylpiperidinylcarbamoyl,3,4-dihydro-2H-benzo[b][1,4]oxazinylcarbamoyl, andditetrahydroquinolylcarbamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-alkylsulfamoyl group” means a sulfamoyl group in which one ortwo hydrogen atoms of the above described “sulfamoyl group” (or R⁷ andR⁸ in “the group: —SO₂NR⁷R⁸”) are substituted with the above described“alkyl groups.” Examples of the mono-/di-alkylsulfamoyl group include a“mono-/di-C₁₋₆ alkylsulfamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-C₁₋₆ alkylsulfamoyl group” include methylsulfamoyl,ethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl,isobutylsulfamoyl, pentylsulfamoyl, isopentylsulfamoyl, hexylsulfamoyl,isohexylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl,dipropylsulfamoyl, diisopropylsulfamoyl, dibutylsulfamoyl,dipentylsulfamoyl, ethylmethylsulfamoyl, methylpropylsulfamoyl,ethylpropylsulfamoyl, butylmethylsulfamoyl, butylethylsulfamoyl, andbutylpropylsulfamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-cycloalkylsulfamoyl group” means a sulfamoyl group in whichone or two hydrogen atoms of the above described “sulfamoyl group” (orR⁷ and R⁸ in “the group: —SO₂NR⁷R⁸”) are substituted with the abovedescribed “cycloalkyl groups.” Examples of themono-/di-cycloalkylsulfamoyl group include a “mono-/di-C₃₋₈cycloalkylsulfamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-C₃₋₈ cycloalkylsulfamoyl group” includecyclopropylsulfamoyl, cyclobutylsulfamoyl, cyclopentylsulfamoyl, andcyclohexylsulfamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-halogenated C₁₋₆ alkylsulfamoyl group” means a substituent inwhich a “C₁₋₆ alkyl group” portion of the above described “mono-/di-C₁₋₆alkylsulfamoyl group” is optionally substituted with one to five halogenatoms. Examples of the mono-/di-halogenated C₁₋₆ alkylsulfamoyl groupinclude trifluoromethylsulfamoyl, 1,1,1-trifluoroethylsulfamoyl, andditrifluoromethylsulfamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-arylsulfamoyl group” means a sulfamoyl group in which one ortwo hydrogen atoms of the above described “sulfamoyl group” (or R⁷ andR⁸ in “the group: —SO₂NR⁷R⁸”) are substituted with the above described“aryl groups.” Examples of the mono-/di-arylsulfamoyl group include a“mono-/di-C₆₋₁₄ arylsulfamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-C₆₋₁₄ arylsulfamoyl group” include phenylsulfamoyl,2-naphthylsulfamoyl, diphenylsulfamoyl, and 2-naphthylphenylsulfamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-aralkylsulfamoyl group” means a sulfamoyl group in which oneor two hydrogen atoms of the above described “sulfamoyl group” (or R⁷and R⁸ in “the group: —SO₂NR⁷R⁸”) are substituted with the abovedescribed “aralkyl groups.” Examples of the mono-/di-aralkylsulfamoylgroup include a “mono-/di-C₇₋₂₀ aralkylsulfamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-C₇₋₂₀ aralkylsulfamoyl group” include benzylsulfamoyl anddibenzylsulfamoyl.

In the present specification, unless otherwise specified, the term“mono-/di-heterocyclic sulfamoyl group” means a sulfamoyl group in whichone or two hydrogen atoms of the above described “sulfamoyl group” (orR⁷ and R⁸ in “the group: —SO₂NR⁷R⁸”) are substituted with the abovedescribed “heterocyclic groups.” Examples of a “heterocyclic ring”portion of the “mono-/di-heterocyclic sulfamoyl group” include a“heteroaryl group,” a “partially hydrogenated fused-ring heteroarylgroup,” and a “non-aromatic heterocyclic group,” which are exemplifiedin the above described “heterocyclic group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-heterocyclic sulfamoyl group” include a“mono-/di-heteroarylsulfamoyl group,” a “mono-/di-partially hydrogenatedfused-ring heteroarylsulfamoyl group,” and a “mono-/di-non-aromaticheterocyclic sulfamoyl group.”

In the present specification, unless otherwise specified, examples ofthe “mono-/di-heteroarylsulfamoyl group,” the “mono-/di-partiallyhydrogenated fused-ring heteroarylsulfamoyl group,” and the“mono-/di-non-aromatic heterocyclic sulfamoyl group” includepyridylsulfamoyl, indolylsulfamoyl, tetrahydropyranylsulfamoyl,dipyridylsulfamoyl, benzofuranylpyridylsulfamoyl,furanylpiperidinylsulfamoyl,3,4-dihydro-2H-benzo[b][1,4]oxazinylsulfamoyl, andditetrahydroquinolylsulfamoyl.

[1-1]

A preferred compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, q, Z, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I) havethe same definitions as those described in the above embodiment [1]; andR¹ each independently represents a halogen atom, a hydroxyl group, anitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group,a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxylgroup, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylcarbonyl group, ahydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonyl group, an—NR⁷R⁸ group, or a —CONR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸ groupand the —CONR⁷R⁸ group have the same definitions as those described inthe above embodiment [1], or a pharmaceutically acceptable salt thereof,or a solvate thereof.

[1-1-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of q, Z, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I) havethe same definitions as those described in the above embodiment [1]; pis an integer of 0 to 3; and R¹ each independently represents a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxylgroup, a halogenated C₁₋₆ alkoxyl group, a hydroxy C₁₋₆ alkyl group, aC₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, an —NR^(7A)R^(8A) group, or a —CONR^(7A)R^(8A)group wherein R^(7A) and R^(8A) in the —NR^(7A)R^(8A) group and the—CONR^(7A)R^(8A) group each independently represent a substituentselected from among a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, ahydroxy C₂₋₇ alkanoyl group, a halogenated C₂₋₇ alkanoyl group, a C₁₋₆alkylsulfonyl group, and a halogenated C₁₋₆ alkylsulfonyl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-1-2-2]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1-1-2]; and R¹ each independently represents a C₂₋₇ alkanoylgroup, and has the same definitions as those described in the aboveembodiment [1-1-2], or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-1-3]

Further preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; p is an integer of 1 to 3; and R¹ each independentlyrepresents a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a hydroxy C₁₋₆alkyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆ alkylthio group, ora C₁₋₆ alkylsulfonyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-1-3-2]

Still further preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1-1-3]; p is an integer of 0 to 3; and R¹ each independentlyrepresents a C₂₋₇ alkanoyl group, and has the same definitions as thosedescribed in the above embodiment [1-1-3], or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-1-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; p is an integer of 1 or 2; and R¹ each independentlyrepresents a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group, and morespecifically, R¹ represents fluorine, chlorine, bromine, a cyano group,a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group,a difluoromethyl group, a trifluoromethyl group, a vinyl group, amethoxy group, an ethoxyethyl group, or the like, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-1-4-2]

More particularly preferably, the compound of the above embodiment [1]is a compound represented by the above formula (I) wherein thedefinition of p, q, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fusedring B in the formula (I) have the same definitions as those describedin the above embodiment [1-1-4]; p is an integer of 0 to 3; and R¹ eachindependently represents a hydroxy C₁₋₆ alkyl group or a C₂₋₇ alkanoylgroup, and has the same definitions as those described in the aboveembodiment [1-1-4], and more specifically, R¹ represents fluorine,chlorine, bromine, a cyano group, a methyl group, an ethyl group, anisopropyl group, a tert-butyl group, a cyclopropyl group, adifluoromethyl group, a trifluoromethyl group, a 1-hydroxyethyl group, avinyl group, an acetyl group, a methoxy group, an ethoxyethyl group, orthe like, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

[1-2]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, q, Z, R¹,R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I) havethe same definitions as those described in the above embodiment [1]; andR² represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-2-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of p, q, Z,R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I)have the same definitions as those described in the above embodiment[1]; and R² represents a hydrogen atom, a C₁₋₆ alkyl group, or ahalogenated C₁₋₆ alkyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-2-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; and R² represents a hydrogen atom or a C₁₋₆ alkyl group,and more specifically, R² represents a hydrogen atom, a methyl group, orthe like, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

[1-2-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; and R² represents a C₁₋₆ alkyl group, and morespecifically, R² represents a methyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-3]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, q, Z, R¹,R², R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I) havethe same definitions as those described in the above embodiment [1]; andR³ each independently represents a halogen atom, a cyano group, a C₁₋₆alkyl group, a halogenated C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, or ahalogenated C₁₋₆ alkoxyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-3-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of p, q, Z,R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I)have the same definitions as those described in the above embodiment[1]; q represents an integer of 0 to 3; and R³ each independentlyrepresents a halogen atom, a cyano group, a C₁₋₆ alkyl group, or a C₁₋₆alkoxyl group, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-3-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; q represents an integer of 0 to 2; and R³ eachindependently represents a halogen atom, a cyano group, a C₁₋₆ alkylgroup, or a C₁₋₆ alkoxyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-3-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; q represents an integer of 0 or 1; and R³ eachindependently represents a hydrogen atom, a halogen atom, or a cyanogroup, and more specifically, R³ represents fluorine, chlorine, a cyanogroup, or the like, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-3-5]

More particularly preferably, the compound of the above embodiment [1]is a compound represented by the above formula (I) wherein thedefinition of p, q, Z, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, ring A, and fusedring B in the formula (I) have the same definitions as those describedin the above embodiment [1]; q represents an integer of 0 or 1; and R³represents a halogen atom, and more specifically, R³ representsfluorine, chlorine, or the like, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-4]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, q, Z, R¹,R², R³, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I) havethe same definitions as those described in the above embodiment [1]; andR⁴ represents a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸ group wherein R⁷ and R⁸in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the same definitions asthose described in the above embodiment [1], a C₆₋₁₄ aryl group, a 3- to14-membered non-aromatic heterocyclic group, or a 5- to 7-memberedmonocyclic heteroaryl group wherein the C₃₋₈ cycloalkyl group, the C₆₋₁₄aryl group, the 3- to 14-membered non-aromatic heterocyclic group, andthe 5- to 7-membered monocyclic heteroaryl group, which are representedby R⁴, are optionally substituted with one to three groups selected fromamong a hydroxyl group, a nitro group, a cyano group, a halogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkylgroup, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonylgroup, a —CONR⁷R⁸ group, an —NR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸group and the —CONR⁷R⁸ group have the same definitions as thosedescribed in the above embodiment [1], a C₆₋₁₄ aryl group, a 3- to14-membered non-aromatic heterocyclic group, and a 5- to 7-memberedmonocyclic heteroaryl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-4-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of p, q, Z,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I)have the same definitions as those described in the above embodiment[1]; and R⁴ represents a halogen atom, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a C₁₋₆ alkoxyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, an —NR^(7A)R^(8A) group wherein R^(8A) and R^(8A)in the —NR^(7A)R^(8A) group have the same definitions as those of R^(7A)and R^(8A) in the above embodiment [1-1-2], a C₆₋₁₄ aryl group, a 3- to14-membered non-aromatic heterocyclic group, or a 5- to 7-memberedmonocyclic heteroaryl group wherein the C₃₋₈ cycloalkyl group, the C₆₋₁₄aryl group, the 3- to 14-membered non-aromatic heterocyclic group, andthe 5- to 7-membered monocyclic heteroaryl group, which are representedby R⁴, are optionally substituted with one to three groups selected fromamong a hydroxyl group, a nitro group, a cyano group, a halogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkylgroup, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonylgroup, a —CONR^(7A)R^(8A) group, an —NR^(7A)R^(8A) group wherein R^(7A)and R^(8A) in the —NR^(7A)R^(8A) group and the —CONR^(7A)R^(8A) grouphave the same definitions as those of R^(7A) and R^(8A) in the aboveembodiment [1-1-2], a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromaticheterocyclic group, and a 5- to 7-membered monocyclic heteroaryl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-4-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; and R⁴ represents a halogen atom, a C₁₋₆ alkyl group, aC₃₋₈ cycloalkyl group, a C₁₋₆ alkoxyl group, a C₁₋₆ alkylsulfonyl group,a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromatic heterocyclic group,or a 5- to 7-membered monocyclic heteroaryl group wherein the C₃₋₈cycloalkyl group, the C₆₋₁₄ aryl group, the 3- to 14-memberednon-aromatic heterocyclic group, and the 5- to 7-membered monocyclicheteroaryl group, which are represented by R⁴, are optionallysubstituted with one to three groups selected from among a hydroxylgroup, a nitro group, a cyano group, a halogen atom, a C₁₋₆ alkyl group,a halogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆alkyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonyl group, a—CONR^(7A)R^(8A) group, an —NR^(7A)R^(8A) group wherein R^(7A) andR^(8A) in the —NR^(7A)R^(8A) group and the —CONR^(7A)R^(8A) group havethe same definitions as those of R^(7A) and R^(8A) in the aboveembodiment [1-1-2], a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromaticheterocyclic group, and a 5- to 7-membered monocyclic heteroaryl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-4-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; and R⁴ represents a halogen atom, a C₆₋₁₄ aryl group, ora 3- to 14-membered non-aromatic heterocyclic group wherein the C₆₋₁₄aryl group and the 3- to 14-membered non-aromatic heterocyclic group,which are represented by R⁴, are optionally substituted with one or twogroups selected from among a halogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, and a C₁₋₆ alkoxylC₁₋₆ alkyl group, and specifically, R⁴ represents chlorine, bromine, aphenyl group, a pyrrolidinyl group, or a morpholinyl group wherein thephenyl group, the pyrrolidinyl group, and the morpholinyl group are eachoptionally substituted with one or two groups selected from amongfluorine, a methyl group, a methoxy group, and a methoxymethyl group,and more specifically, R⁴ represents chlorine, bromine, phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-methoxymethylphenyl,3-methoxymethylphenyl, 4-methoxymethylphenyl, pyrrolidinyl,2-fluoropyrrolidinyl, 3-fluoropyrrolidinyl, 2-methylpyrrolidinyl,3-methylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl,3-trifluoromethylpyrrolidinyl, 2-methoxypyrrolidinyl,3-methoxypyrrolidinyl, 2-methoxymethylpyrrolidinyl,3-methoxymethylpyrrolidinyl, 2-fluoromorpholinyl, 3-fluoromorpholinyl,3,5-difluoromorpholinyl, 2,6-difluoromorpholinyl, 2-methylmorpholinyl,3-methylmorpholinyl, 3,5-dimethylmorpholinyl, 2,6-dimethylmorpholinyl,2-methoxymethylmorpholinyl, 3-methoxymethylmorpholinyl,3,5-di(methoxymethyl)morpholinyl, 2,6-di(methoxymethyl)morpholinyl, orthe like, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

[1-4-4-2]

More particularly preferably, the compound of the above embodiment [1]is a compound represented by the above formula (I) wherein thedefinition of p, q, Z, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, ring A, and fusedring B in the formula (I) have the same definitions as those describedin the above embodiment [1-4-4]; and R⁴ represents a halogen atom, aC₆₋₁₄ aryl group, a 3- to 14-membered non-aromatic heterocyclic group,or a 5- to 7-membered monocyclic heteroaryl group wherein the C₆₋₁₄ arylgroup, the 3- to 14-membered non-aromatic heterocyclic group, and the 5-to 7-membered monocyclic heteroaryl group, which are represented by R⁴,are optionally substituted with one or two groups selected from among ahalogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₁₋₆alkoxyl group, and a C₁₋₆ alkoxyl C₁₋₆ alkyl group, and specifically, R⁴represents chlorine, bromine, a phenyl group, a pyridinyl group, apyrrolidinyl group, or a morpholinyl group wherein the phenyl group, thepyridinyl group, the pyrrolidinyl group, and the morpholinyl group areeach optionally substituted with one or two groups selected from amongfluorine, a methyl group, a methoxy group, and a methoxymethyl group,and more specifically, R⁴ represents chlorine, bromine, phenyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-methoxymethylphenyl, 3-methoxymethylphenyl, 4-methoxymethylphenyl,pyrrolidinyl, 2-fluoropyrrolidinyl, 3-fluoropyrrolidinyl,2-methylpyrrolidinyl, 3-methylpyrrolidinyl,2-trifluoromethylpyrrolidinyl, 3-trifluoromethylpyrrolidinyl,2-methoxypyrrolidinyl, 3-methoxypyrrolidinyl,2-methoxymethylpyrrolidinyl, 3-methoxymethylpyrrolidinyl,2-fluoromorpholinyl, 3-fluoromorpholinyl, 3,5-difluoromorpholinyl,2,6-difluoromorpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl,3,5-dimethylmorpholinyl, 2,6-dimethylmorpholinyl,2-methoxymethylmorpholinyl, 3-methoxymethylmorpholinyl,3,5-di(methoxymethyl)morpholinyl, 2,6-di(methoxymethyl)morpholinyl, orthe like, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

[1-4-5]

Even more particularly preferably, the compound of the above embodiment[1] is a compound represented by the above formula (I) wherein thedefinition of p, q, Z, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, ring A, and fusedring B in the formula (I) have the same definitions as those describedin the above embodiment [1]; and R⁴ represents a C₆₋₁₄ aryl group, a 3-to 14-membered non-aromatic heterocyclic group, or a 5- to 7-memberedmonocyclic heteroaryl group wherein the C₆₋₁₄ aryl group, the 3- to14-membered non-aromatic heterocyclic group, and the 5- to 7-memberedmonocyclic heteroaryl group, which are represented by R⁴, are optionallysubstituted with one or two groups selected from among a halogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group,and a C₁₋₆ alkoxyl C₁₋₆ alkyl group, and specifically, R⁴ representsphenyl, 2-pyridinyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,5-difluorophenyl, 2-methylphenyl, 2-methoxyphenyl, pyrrolidinyl,3-fluoropyrrolidinyl, 2-methylpyrrolidinyl,2-trifluoromethylpyrrolidinyl, 2-methoxymethylpyrrolidinyl, or2,6-dimethylmorpholinyl, or a pharmaceutically acceptable salt thereof,or a solvate thereof.

[1-5]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, q, Z, R¹,R², R³, R⁴, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I) havethe same definitions as those described in the above embodiment [1]; andR⁵ represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, or a halogenatedC₁₋₆ alkoxyl group, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-5-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of p, q, Z,R¹, R², R³, R⁴, R⁶, R⁷, R⁸, ring A, and fused ring B in the formula (I)have the same definitions as those described in the above embodiment[1]; and R⁵ represents a hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup, or a C₁₋₆ alkoxyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-5-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by above the formula (I) wherein the definition ofp, q, Z, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; and R⁵ represents a hydrogen atom, a halogen atom, or aC₁₋₆ alkyl group, and more specifically, R⁵ represents a hydrogen atom,fluorine, a methyl group, or the like, or a pharmaceutically acceptablesalt thereof, or a solvate thereof.

[1-5-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, ring A, and fused ring B in theformula (I) have the same definitions as those described in the aboveembodiment [1]; and R⁵ represents a hydrogen atom or a halogen atom, andmore specifically, R⁵ represents a hydrogen atom, fluorine, or the like,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-6]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, q, Z, R¹,R², R³, R⁴, R⁵, R⁷, R⁸, and fused ring B in the formula (I) have thesame definitions as those described in the above embodiment [1];

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-6-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of p, q, Z,R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and fused ring B in the formula (I) have thesame definitions as those described in the above embodiment [1];

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-6-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and fused ring B in the formula (I)have the same definitions as those described in the above embodiment[1];

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-6-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, q, Z, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and fused ring B in the formula (I)have the same definitions as those described in the above embodiment[1];

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom or a C₁₋₆ alkyl group, and morespecifically, R⁶ represents a hydrogen atom, a methyl group, or thelike, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[1-6-5]

More particularly preferably, the compound of the above embodiment [1]is a compound represented by the above formula (I) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and fused ring B inthe formula (I) have the same definitions as those described in theabove embodiment [1]; ring A and R⁶ have the same definitions as thosedescribed in the above embodiment [1-6-4]; and a specific ring A group,in which the definitions of the above described p, R¹, and ring A arecombined, represents a 1-methyl-1H-imidazol-4-yl group, a4-(difluoromethyl)-5-ethylthiazol-2-yl group, a4-(difluoromethyl)-5-vinylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(difluoromethyl)thiazol-2-ylgroup, a 4-(trifluoromethyl)thiazol-2-yl group, a4-(trifluoromethyl)thiazol-2-yl group, a 4,5-dimethylthiazol-2-yl group,a 4-tert-butylthiazol-2-yl group, a 4-ethylthiazol-2-yl group, a4-cyanothiazol-2-yl group, a 4-methylthiazol-2-yl group, a4-methylthiazol-2-yl group, a 5-(2-ethoxyethyl)-4-methylthiazol-2-ylgroup, a 5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-methylthiazol-2-yl group, a 5-bromo-4-methylthiazol-2-ylgroup, a 5-methylthiazol-2-yl group, a thiazol-2-yl group, a2,5-dimethyl-thiazol-4-yl group, a 2-methylthiazol-4-yl group, a5-(1-hydroxyethyl)-2-methylthiazol-4-yl group, a5-acetyl-2-methylthiazol-4-yl group, a 5-bromo-2-methylthiazol-4-ylgroup, a thiazol-4-yl group, a 3-isopropyl-1,2,4-thiadiazol-5-yl group,a 3-methyl-1,2,4-thiadiazol-5-yl group, a 5-ethyl-1,3,4-thiadiazol-2-ylgroup, a 5-methyl-1,3,4-thiadiazol-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 4,6-dimethylpyrimidin-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 2,5,6-trimethylpyrimidin-4-yl group, a2,5-dimethylpyrimidin-4-yl group, a 2,6-dimethylpyrimidin-4-yl group, a2,6-dimethoxypyrimidin-4-yl group, a 2-methylpyrimidin-4-yl group, a2-methoxypyrimidin-4-yl group, a 5,6-dimethylpyrimidin-4-yl group, a5-chloro-2-methylpyrimidin-4-yl group, a 5-chloropyrimidin-4-yl group, a5-fluoro-2-methylpyrimidin-4-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a5-fluoro-6-methylpyrimidin-4-yl group, a 5-methylpyrimidin-4-yl group, a5-methoxypyrimidin-4-yl group, a 6-methylpyrimidin-4-yl group, a6-methoxy-5-methylpyrimidin-4-yl group, a 4-methylpyridazin-3-yl group,a 5-methylpyridazin-3-yl group, a 6-methylpyridazin-3-yl group, apyridazin-3-yl group, a 3-cyanopyridin-2-yl group, a3-cyano-pyridin-2-yl group, a 3-methylpyridin-2-yl group, a3-methoxypyridin-2-yl group, a 4,6-dimethylpyridin-2-yl group, a4-fluoropyridin-2-yl group, a 4-methylpyridin-2-yl group, a4-methylpyridin-2-yl group, a 4-methoxypyridin-2-yl group, a4-methoxy-pyridin-2-yl group, a 5-cyanopyridin-2-yl group, a5-fluoropyridin-2-yl group, a 5-methylpyridin-2-yl group, a5-methylpyridin-2-yl group, a 6-(trifluoromethyl)pyridin-2-yl group, a6-cyano-pyridin-2-yl group, a 6-methylpyridin-2-yl group, a6-methoxypyridin-2-yl group, a 3,6-dimethylpyrazin-2-yl group, a3,6-dimethyl-pyrazin-2-yl group, a 3-methylpyrazin-2-yl group, a3-methoxypyrazin-2-yl group, a 5-methylpyrazin-2-yl group, a6-methylpyrazin-2-yl group, or a 6-methoxypyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-7]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the formula (I) wherein the definition of p, Z, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and ring A in the formula (I) have the samedefinitions as those described in the above embodiment [1]; q is aninteger represented by 0 to 3; and fused ring B represented by thefollowing partial structural formula (III):

is selected from the group consisting of the following:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-7-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein the definition of p, Z, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and ring A in the formula (I) have the samedefinitions as those described in the above embodiment [1]; q is aninteger represented by 0 to 2; and fused ring B represented by thefollowing partial structural formula (III):

is selected from the group consisting of the following:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-7-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and ring A in the formula (I) havethe same definitions as those described in the above embodiment [1]; qis an integer represented by 0 or 1; and fused ring B represented by thefollowing partial structural formula (III):

is selected from the group consisting of the following:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-7-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein the definition ofp, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and ring A in the formula (I) havethe same definitions as those described in the above embodiment [1]; qis an integer represented by 0 or 1; and fused ring B represented by thefollowing partial structural formula (III):

is selected from the group consisting of the following:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1a]

The compound of the above embodiment [1] is a compound represented bythe following formula (I):

wherein the definition of p, q, Z, R¹, R³, R⁴, R⁵, R⁶, ring Arepresented by the partial structural formula (II), and fused ring Brepresented by the partial structural formula (III) in the formula (I)have the same definitions as those described in the above embodiment[1]; and R² represents a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkylgroup, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1a-1]

Preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein p represents an integer of0 to 4; q represents an integer of 0 to 3; Z represents N or CR⁵; R¹ hasthe same definitions as those described in the above embodiment [1-1];R² represents a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, or aC₁₋₆ alkoxyl C₁₋₆ alkyl group; R³ has the same definitions as thosedescribed in the above embodiment [1-3]; R⁴ has the same definitions asthose described in the above embodiment [1-4]; R⁵ has the samedefinitions as those described in the above embodiment [1-5]; ring Arepresented by the partial structural formula (II) and R⁶ have the samedefinitions as those described in the above embodiment [1-6]; and fusedring B represented by the partial structural formula (III) has the samedefinitions as those described in the above embodiment [1-7], or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1a-1-2]

More preferably, the compound of the above embodiment [1] is a compoundrepresented by the above formula (I) wherein p represents an integer of0 to 3; q represents an integer of 0 to 2; Z represents N or CR⁵; R¹ hasthe same definitions as those described in the above embodiment[1-1-2-2]; R² represents a C₁₋₆ alkyl group or a halogenated C₁₋₆ alkylgroup; R³ has the same definitions as those described in the aboveembodiment [1-3-2]; R⁴ has the same definitions as those described inthe above embodiment [1-4-2]; R⁵ has the same definitions as thosedescribed in the above embodiment [1-5-2]; ring A represented by thepartial structural formula (II) and R⁶ have the same definitions asthose described in the above embodiment [1-6-2]; and fused ring Brepresented by the partial structural formula (III) has the samedefinitions as those described in the above embodiment [1-7-2], or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1a-1-3]

Even more preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein p represents aninteger of 0 to 3; q represents an integer of 0 or 1; Z represents N orCR⁵; R¹ has the same definitions as those described in the aboveembodiment [1-1-3-2]; R² represents a C₁₋₆ alkyl group; R³ has the samedefinitions as those described in the above embodiment [1-3-3]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-3];R⁵ has the same definitions as those described in the above embodiment[1-5-3]; ring A represented by the partial structural formula (II) andR⁶ have the same definitions as those described in the above embodiment[1-6-3]; and fused ring B represented by the partial structural formula(III) has the same definitions as those described in the aboveembodiment [1-7-3], or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1a-1-4]

Particularly preferably, the compound of the above embodiment [1] is acompound represented by the above formula (I) wherein p represents aninteger of 0 to 3; q represents an integer of 0 or 1; Z represents N orCR⁵; R¹ has the same definitions as those described in the aboveembodiment [1-1-4-2]; R² represents a C₁₋₆ alkyl group; R³ has the samedefinitions as those described in the above embodiment [1-3-4]; R⁴ hasthe same definitions as those described in the above embodiment[1-4-4-2]; R⁵ has the same definitions as those described in the aboveembodiment [1-5-4]; ring A represented by the partial structural formula(II) and R⁶ have the same definitions as those described in the aboveembodiment [1-6-4]; and fused ring B represented by the partialstructural formula (III) has the same definitions as those described inthe above embodiment [1-7-4], or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1a-1-5]

More particularly preferably, the compound of the above embodiment [1]is a compound represented by the above formula (I) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, R⁶, ring A represented by thepartial structural formula (II), and fused ring B represented by thepartial structural formula (III) in the formula (I) have the samedefinitions as those described in the above embodiment [1a-1-4]; and aspecific ring A group, in which the definitions of the above describedp, R¹, and ring A are combined, represents a 1-methyl-1H-imidazol-4-ylgroup, a 4-(difluoromethyl)-5-ethylthiazol-2-yl group, a4-(difluoromethyl)-5-vinylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(difluoromethyl)thiazol-2-ylgroup, a 4-(trifluoromethyl)thiazol-2-yl group, a4-(trifluoromethyl)thiazol-2-yl group, a 4,5-dimethylthiazol-2-yl group,a 4-tert-butylthiazol-2-yl group, a 4-ethylthiazol-2-yl group, a4-cyanothiazol-2-yl group, a 4-methylthiazol-2-yl group, a4-methylthiazol-2-yl group, a 5-(2-ethoxyethyl)-4-methylthiazol-2-ylgroup, a 5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-methylthiazol-2-yl group, a 5-bromo-4-methylthiazol-2-ylgroup, a 5-methylthiazol-2-yl group, a thiazol-2-yl group, a2,5-dimethyl-thiazol-4-yl group, a 2-methylthiazol-4-yl group, a5-(1-hydroxyethyl)-2-methylthiazol-4-yl group, a5-acetyl-2-methylthiazol-4-yl group, a 5-bromo-2-methylthiazol-4-ylgroup, a thiazol-4-yl group, a 3-isopropyl-1,2,4-thiadiazol-5-yl group,a 3-methyl-1,2,4-thiadiazol-5-yl group, a 5-ethyl-1,3,4-thiadiazol-2-ylgroup, a 5-methyl-1,3,4-thiadiazol-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 4,6-dimethylpyrimidin-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 2,5,6-trimethylpyrimidin-4-yl group, a2,5-dimethylpyrimidin-4-yl group, a 2,6-dimethylpyrimidin-4-yl group, a2,6-dimethoxypyrimidin-4-yl group, a 2-methylpyrimidin-4-yl group, a2-methoxypyrimidin-4-yl group, a 5,6-dimethylpyrimidin-4-yl group, a5-chloro-2-methylpyrimidin-4-yl group, a 5-chloropyrimidin-4-yl group, a5-fluoro-2-methylpyrimidin-4-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a5-fluoro-6-methylpyrimidin-4-yl group, a 5-methylpyrimidin-4-yl group, a5-methoxypyrimidin-4-yl group, a 6-methylpyrimidin-4-yl group, a6-methoxy-5-methylpyrimidin-4-yl group, a 4-methylpyridazin-3-yl group,a 5-methylpyridazin-3-yl group, a 6-methylpyridazin-3-yl group, apyridazin-3-yl group, a 3-cyanopyridin-2-yl group, a3-cyano-pyridin-2-yl group, a 3-methylpyridin-2-yl group, a3-methoxypyridin-2-yl group, a 4,6-dimethylpyridin-2-yl group, a4-fluoropyridin-2-yl group, a 4-methylpyridin-2-yl group, a4-methylpyridin-2-yl group, a 4-methoxypyridin-2-yl group, a4-methoxy-pyridin-2-yl group, a 5-cyanopyridin-2-yl group, a5-fluoropyridin-2-yl group, a 5-methylpyridin-2-yl group, a5-methylpyridin-2-yl group, a 6-(trifluoromethyl)pyridin-2-yl group, a6-cyano-pyridin-2-yl group, a 6-methylpyridin-2-yl group, a6-methoxypyridin-2-yl group, a 3,6-dimethylpyrazin-2-yl group, a3,6-dimethyl-pyrazin-2-yl group, a 3-methylpyrazin-2-yl group, a3-methoxypyrazin-2-yl group, a 5-methylpyrazin-2-yl group, a6-methylpyrazin-2-yl group, or a 6-methoxypyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-8]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-a):

wherein the definition of q, Z, R², R³, R⁴, and R⁵ in the formula (I-a)have the same definitions as those described in the above embodiment[1]; p represents an integer of 0 to 2; R¹ each independently representsa halogen atom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxylgroup, a C₁₋₆ alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group,a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group,or a —CONR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the—CONR⁷R⁸ group have the same definitions as those described in the aboveembodiment [1];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-8-2]

Preferably, the compound of the above embodiment [1-8] is a compoundrepresented by the above formula (I-a) wherein the definition of q, Z,R², R³, R⁴, and R⁵ in the formula (I-a) have the same definitions asthose described in the above embodiment [1]; p represents an integer of0 to 2; R¹ each independently represents a halogen atom, a hydroxylgroup, a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₁₋₆alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ group wherein R⁷ andR⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the same definitionsas those described in the above embodiment [1];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-8-3]

More preferably, the compound of the above embodiment [1-8] is acompound represented by the above formula (I-a) wherein the definitionof q, Z, R², R³, R⁴, and R⁵ in the formula (I-a) have the samedefinitions as those described in the above embodiment [1]; p representsan integer of 0 to 2; R¹ each independently represents a halogen atom, ahydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, a —CONR^(7A)R^(8A) group, or an —NR^(7A)R^(8A)group wherein R^(7A) and R^(8A) in the —NR^(7A)R^(8A) group and the—CONR^(7A)R^(BA) group have the same definitions as those of R^(7A) andR^(8A) in the above embodiment [1-1-2];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-8-3-2]

Even more preferably, the compound of the above embodiment [1-8] is acompound represented by the above formula (I-a) wherein the definitionof p, q, Z, R², R³, R⁴, R⁵, R⁶, and ring A′ represented by the partialstructural formula (II′) in the formula (I-a) have the same definitionsas those described in the above embodiment [1-8-3]; and R¹ eachindependently represents a hydroxy C₁₋₆ alkyl group, and has the samedefinitions as those described in the above embodiment [1-8-3], or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-8-4]

Further preferably, the compound of the above embodiment [1-8] is acompound represented by the above formula (I-a) wherein the definitionof q, Z, R², R³, R⁴, and R⁵ in the formula (I-a) have the samedefinitions as those described in the above embodiment [1]; p representsan integer of 1 or 2; R¹ each independently represents a halogen atom, ahydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, or aC₁₋₆ alkylsulfonyl group;

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-8-4-2]

Still further preferably, the compound of the above embodiment [1-8] isa compound represented by the above formula (I-a) wherein the definitionof q, Z, R², R³, R⁴, R⁵, R⁶, and ring A′ represented by the partialstructural formula (II′) in the formula (I-a) have the same definitionsas those described in the above embodiment [1-8-4]; p represents aninteger of 0 to 2; and R¹ each independently represents a hydroxy C₁₋₆alkyl group, and has the same definitions as those described in theabove embodiment [1-8-4], or a pharmaceutically acceptable salt thereof,or a solvate thereof.

[1-8-5]

Particularly preferably, the compound of the above embodiment [1-8] is acompound represented by the above formula (I-a) wherein the definitionof q, Z, R², R³, R⁴, and R⁵ in the formula (I-a) have the samedefinitions as those described in the above embodiment [1]; p representsan integer of 1 or 2; and R¹ each independently represents a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, or a C₁₋₆ alkoxylC₁₋₆ alkyl group, and more specifically, R¹ represents chlorine,bromine, a cyano group, a methyl group, an ethyl group, an isopropylgroup, a cyclopropyl group, a vinyl group, a difluoromethyl group, atrifluoromethyl group, an ethoxyethyl group, or the like;

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom or a C₁₋₆ alkyl group, and morespecifically, R⁶ represents a hydrogen atom, a methyl group, or thelike, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[1-8-5-2]

More particularly preferably, the compound of the above embodiment [1-8]is a compound represented by the above formula (I-a) wherein thedefinition of q, Z, R², R³, R⁴, R⁵, R⁶, and ring A′ represented by thepartial structural formula (II′) in the formula (I-a) have the samedefinitions as those described in the above embodiment [1-8-5]; prepresents an integer of 0 to 2; and R¹ each independently represents ahydroxy C₁₋₆ alkyl group or a C₂₋₇ alkanoyl group, and has the samedefinitions as those described in the above embodiment [1-8-5], and morespecifically, R¹ represents chlorine, bromine, a cyano group, a methylgroup, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a vinyl group, a difluoromethyl group, atrifluoromethyl group, a 1-hydroxyethyl group, an ethoxyethyl group, anacetyl group, or the like, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-8-6]

Even more particularly preferably, the compound of the above embodiment[1-8] is a compound represented by the above formula (I-a) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, R⁶, and ring A′ in theformula (I-a) have the same definitions as those described in the aboveembodiment [1-8-5-2]; and a specific ring A′ group, in which thedefinitions of the above described p, R¹, and ring A′ are combined,represents a 1-methyl-1H-imidazol-4-yl group, a4-(difluoromethyl)-5-ethylthiazol-2-yl group, a4-(difluoromethyl)-5-vinylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(trifluoromethyl)thiazol-2-ylgroup, a 4,5-dimethylthiazol-2-yl group, a 4-tert-butylthiazol-2-ylgroup, a 4-cyanothiazol-2-yl group, a 4-methylthiazol-2-yl group, a5-(2-ethoxyethyl)-4-methylthiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-methylthiazol-2-yl group, a 5-bromo-4-methylthiazol-2-ylgroup, a 5-methylthiazol-2-yl group, a thiazol-2-yl group, a2,5-dimethyl-thiazol-4-yl group, a 2-methylthiazol-4-yl group, a5-(1-hydroxyethyl)-2-methylthiazol-4-yl group, a5-acetyl-2-methylthiazol-4-yl group, a 5-bromo-2-methylthiazol-4-ylgroup, a thiazol-4-yl group, a 3-isopropyl-1,2,4-thiadiazol-5-yl group,a 3-methyl-1,2,4-thiadiazol-5-yl group, a 5-ethyl-1,3,4-thiadiazol-2-ylgroup, or a 5-methyl-1,3,4-thiadiazol-2-yl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-8a]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-a):

wherein the definition of q, Z, R³, R⁴, R⁵, and R⁶ in the formula (I-a)have the same definitions as those described in the above embodiment[1]; p, R¹, R⁶, and ring A′ represented by the partial structuralformula (II′) have the same definitions as those described in the aboveembodiment [1-8]; and R² represents a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[1-8a-2]

Preferably, the compound of the above embodiment [1-8a] is a compoundrepresented by the above formula (I-a) wherein R³ has the samedefinitions as those described in the above embodiment [1-3]; R⁴ has thesame definitions as those described in the above embodiment [1-4]; Z andR⁵ have the same definitions as those described in the above embodiment[1-5]; q has the same definitions as those described in the aboveembodiment [1-7]; p, R¹, R⁶, and ring A′ represented by the partialstructural formula (II′) have the same definitions as those described inthe above embodiment [1-8-2]; and R² represents a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-8a-3]

More preferably, the compound of the above embodiment [1-8a] is acompound represented by the above formula (I-a) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-2]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-2];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-2]; q has the same definitions as those described in theabove embodiment [1-7-2]; p, R¹, R⁶, and ring A′ represented by thepartial structural formula (II′) have the same definitions as thosedescribed in the above embodiment [1-8-3-2]; and R² represents a C₁₋₆alkyl group or a halogenated C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-8a-4]

Even more preferably, the compound of the above embodiment [1-8a] is acompound represented by the above formula (I-a) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-3]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-3];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-3]; q has the same definitions as those described in theabove embodiment [1-7-3]; p, R¹, R⁶, and ring A′ represented by thepartial structural formula (II′) have the same definitions as thosedescribed in the above embodiment [1-8-4-2]; and R² represents a C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

[1-8a-5]

Particularly preferably, the compound of the above embodiment [1-8a] isa compound represented by the above formula (I-a) wherein R³ has thesame definitions as those described in the above embodiment [1-3-4]; Zand R⁵ have the same definitions as those described in the aboveembodiment [1-5-4]; q has the same definitions as those described in theabove embodiment [1-7-4]; p, R¹, R⁶, and ring A′ represented by thepartial structural formula (II′) have the same definitions as thosedescribed in the above embodiment [1-8-5-2]; R² represents a C₁₋₆ alkylgroup, and more specifically, R² represents a methyl group or the like;and R⁴ represents a C₆₋₁₄ aryl group or a 3- to 14-membered non-aromaticheterocyclic group wherein the C₆₋₁₄ aryl group and the 3- to14-membered non-aromatic heterocyclic group, which are represented byR⁴, are optionally substituted with one or two groups selected fromamong a halogen atom, a C₁₋₆ alkoxyl group, and a C₁₋₆ alkoxyl C₁₋₆alkyl group, and specifically, R⁴ represents phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, pyrrolidinyl, 2-fluoropyrrolidinyl,3-fluoropyrrolidinyl, 2-methoxypyrrolidinyl, 3-methoxypyrrolidinyl,2-methoxymethylpyrrolidinyl, 3-methoxymethylpyrrolidinyl, or the like,and preferably represents phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,5-difluorophenyl, 2-methoxyphenyl, pyrrolidinyl, or2-methoxymethylpyrrolidinyl, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-8a-6]

More particularly preferably, the compound of the above embodiment[1-8a] is a compound represented by the above formula (I-a) wherein p,q, Z, R¹, R², R³, R⁴, R⁵, R⁶, and ring A′ have the same definitions asthose described in the above embodiment [1-8a-5]; and a specific ring A′group, in which the definitions of the above described p, R¹, and ringA′ are combined, represents a 1-methyl-1H-imidazol-4-yl group, a4-(difluoromethyl)-5-ethylthiazol-2-yl group, a4-(difluoromethyl)-5-vinylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(trifluoromethyl)thiazol-2-ylgroup, a 4,5-dimethylthiazol-2-yl group, a 4-tert-butylthiazol-2-ylgroup, a 4-cyanothiazol-2-yl group, a 4-methylthiazol-2-yl group, a5-(2-ethoxyethyl)-4-methylthiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-methylthiazol-2-yl group, a 5-bromo-4-methylthiazol-2-ylgroup, a 5-methylthiazol-2-yl group, a thiazol-2-yl group, a2,5-dimethyl-thiazol-4-yl group, a 2-methylthiazol-4-yl group, a5-(1-hydroxyethyl)-2-methylthiazol-4-yl group, a5-acetyl-2-methylthiazol-4-yl group, a 5-bromo-2-methylthiazol-4-ylgroup, a thiazol-4-yl group, a 3-isopropyl-1,2,4-thiadiazol-5-yl group,a 3-methyl-1,2,4-thiadiazol-5-yl group, a 5-ethyl-1,3,4-thiadiazol-2-ylgroup, or a 5-methyl-1,3,4-thiadiazol-2-yl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-9]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-b):

wherein the definition of Z, R², R³, R⁴, and R⁵ in the formula (I-b)have the same definitions as those described in the above embodiment[1]; p represents an integer of 0 to 2; q represents an integer of 0 to3; R¹ each independently represents a halogen atom, a hydroxyl group, anitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group,a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxylgroup, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylcarbonyl group, ahydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfinyl group, aC₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ group whereinR⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the samedefinitions as those described in the above embodiment [1];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-9-2]

Preferably, the compound of the above embodiment [1-9] is a compoundrepresented by the above formula (I-b) wherein the definition of Z, R²,R³, R⁴, and R⁵ in the formula (I-b) have the same definitions as thosedescribed in the above embodiment [1]; p represents an integer of 0 to2; q represents an integer of 0 to 3; R¹ each independently represents ahalogen atom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxylgroup, a C₁₋₆ alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group,a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ group whereinR⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the samedefinitions as those described in the above embodiment [1];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-9-3]

More preferably, the compound of the above embodiment [1-9] is acompound represented by the above formula (I-b) wherein the definitionof Z, R², R³, R⁴, and R⁵ in the formula (I-b) have the same definitionsas those described in the above embodiment [1]; p represents an integerof 0 to 2; q represents an integer of 0 to 2; R¹ each independentlyrepresents a halogen atom, a hydroxyl group, a nitro group, a cyanogroup, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenatedC₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoylgroup, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonyl group, a—CONR^(2A)R^(8A) group, or an —NR^(7A)R^(8A) group wherein R^(7A) andR^(8A) in the —NR^(7A)R^(8A) group and the —CONR^(7A)R^(8A) group havethe same definitions as those of R^(7A) and R^(8A) in the aboveembodiment [1-1-2]);

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-9-4]

Even more preferably, the compound of the above embodiment [1-9] is acompound represented by the above formula (I-b) wherein the definitionof Z, R², R³, R⁴, and R⁵ in the formula (I-b) have the same definitionsas those described in the above embodiment [1]; p represents an integerof 1 or 2; q represents an integer of 0 to 2; R¹ each independentlyrepresents a halogen atom, a hydroxyl group, a nitro group, a cyanogroup, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenatedC₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoylgroup, a C₁₋₆ alkylthio group, or a C₁₋₆ alkylsulfonyl group;

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[1-9-4-2]

Further preferably, the compound of the above embodiment [1-9] is acompound represented by the above formula (I-b) wherein the definitionof q, Z, R¹, R², R³, R⁴, R⁵, R⁶, and ring A′ represented by the partialstructural formula (II′) in the formula (I-b) have the same definitionsas those described in the above embodiment [1-9-4]; and p represents aninteger of 0 to 2, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-9-5]

Particularly preferably, the compound of the above embodiment [1-9] is acompound represented by above the formula (I-b) wherein the definitionof Z, R², R³, R⁴, and R⁵ in the formula (I-b) have the same definitionsas those described in the above embodiment [1]; p represents an integerof 1 or 2; q represents an integer of 0 or 1; R¹ each independentlyrepresents a halogen atom, a C₁₋₆ alkyl group, or a halogenated C₁₋₆alkyl group, and more specifically, R¹ represents chlorine, a methylgroup, an ethyl group, a difluoromethyl group, a trifluoromethyl group,or the like;

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom or a C₁₋₆ alkyl group, and morespecifically, R⁶ represents a hydrogen atom, a methyl group, or thelike, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[1-9-5-2]

More particularly preferably, the compound of the above embodiment [1-9]is a compound represented by the above formula (I-b) wherein thedefinition of q, Z, R¹, R², R³, R⁴, and R⁵ in the formula (I-b) have thesame definitions as those described in the above embodiment [1-9-5]; prepresents an integer of 0 to 2; ring A′ represented by the followingpartial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom or a C₁₋₆ alkyl group, and morespecifically, R⁶ represents a hydrogen atom, a methyl group, or thelike, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[1-9-6]

Even more particularly preferably, the compound of the above embodiment[1-9] is a compound represented by the above formula (I-b) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, R⁶, and ring A′ in theformula (I-b) have the same definitions as those described in the aboveembodiment [1-9-5-2]; and a specific ring A′ group, in which thedefinitions of the above described p, R¹, and ring A′ are combined,represents a 1-methyl-1H-imidazol-4-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(trifluoromethyl)thiazol-2-ylgroup, a 4-ethylthiazol-2-yl group, a 4-methylthiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-9a]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-b):

wherein the definition of q, Z, R³, R⁴, R⁵, and R⁶ in the formula (I-b)have the same definitions as those described in the above embodiment[1]; p, R¹, R⁶, and ring A′ represented by the partial structuralformula (II′) have the same definitions as those described in the aboveembodiment [1-9]; and R² represents a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[1-9a-2]

Preferably, the compound of the above embodiment [1-9a] is a compoundrepresented by the above formula (I-b) wherein R³ has the samedefinitions as those described in the above embodiment [1-3]; R⁴ has thesame definitions as those described in the above embodiment [1-4]; Z andR⁵ have the same definitions as those described in the above embodiment[1-5]; q has the same definitions as those described in the aboveembodiment [1-7]; p, R¹, R⁶, and ring A′ represented by the partialstructural formula (II′) have the same definitions as those described inthe above embodiment [1-9-2]; and R² represents a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-9a-3]

More preferably, the compound of the above embodiment [1-9a] is acompound represented by the above formula (I-b) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-2]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-2];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-2]; q has the same definitions as those described in theabove embodiment [1-7-2]; p, R¹, R⁶, and ring A′ represented by thepartial structural formula (II′) have the same definitions as thosedescribed in the above embodiment [1-9-3]; and R² represents a C₁₋₆alkyl group or a halogenated C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-9a-4]

Even more preferably, the compound of the above embodiment [1-9a] is acompound represented by the above formula (I-b) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-3]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-3];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-3]; q has the same definitions as those described in theabove embodiment [1-7-3]; p, R¹, R⁶, and ring A′ represented by thepartial structural formula (II′) have the same definitions as thosedescribed in the above embodiment [1-9-4-2]; and R² represents a C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.

[1-9a-5]

Particularly preferably, the compound of the above embodiment [1-9a] isa compound represented by the above formula (I-b) wherein R³ has thesame definitions as those described in the above embodiment [1-3-4]; Zand R⁵ have the same definitions as those described in the aboveembodiment [1-5-4]; q has the same definitions as those described in theabove embodiment [1-7-4]; p, R¹, R⁶, and ring A′ represented by thepartial structural formula (II′) have the same definitions as thosedescribed in the above embodiment [1-9-5-2]; R² represents a C₁₋₆ alkylgroup, and more specifically, R² represents a methyl group or the like;and R⁴ represents a C₆₋₁₄ aryl group, or a 3- to 14-memberednon-aromatic heterocyclic group wherein the C₆₋₁₄ aryl group and the 3-to 14-membered non-aromatic heterocyclic group, which are represented byR⁴, are each optionally substituted with one or two groups selected fromamong a halogen atom, a C₁₋₆ alkyl group, and a C₁₋₆ alkoxyl group, andspecifically, R⁴ represents phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,5-difluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,5-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,pyrrolidinyl, 2-fluoropyrrolidinyl, 3-fluoropyrrolidinyl,2-methoxypyrrolidinyl, 3-methoxypyrrolidinyl, 2-methylpyrrolidinyl,3-methylpyrrolidinyl, morpholinyl, 2-methylmorpholinyl,3-methylmorpholinyl, 2,6-dimethylmorpholinyl, 3,5-dimethylmorpholinyl,or the like, and R⁴ preferably represents phenyl, 3-fluorophenyl,2-methoxyphenyl, pyrrolidinyl, 3-fluoropyrrolidinyl,2-methylpyrrolidinyl, or 2,6-dimethylmorpholinyl, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-9a-6]

More particularly preferably, the compound of the above embodiment[1-9a] is a compound represented by the above formula (I-b) wherein p,q, Z, R¹, R², R³, R⁴, R⁵, R⁶, and ring A′ have the same definitions asthose described in the above embodiment [1-9a-5]; and a specific ring A′group, in which the definitions of the above described p, R¹, and ringA′ are combined, represents a 1-methyl-1H-imidazol-4-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(trifluoromethyl)thiazol-2-ylgroup, a 4-ethylthiazol-2-yl group, a 4-methylthiazol-2-yl group, or a5-chloro-4-(difluoromethyl)thiazol-2-yl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[1-10]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-c):

wherein the definition of q, Z, R², R³, R⁴, and R⁵ in the formula (I-c)have the same definitions as those described in the above embodiment[1]; p represents an integer of 0 to 4; R¹ each independently representsa halogen atom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxylgroup, a C₁₋₆ alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group,a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group,or a —CONR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the—CONR⁷R⁸ group have the same definitions as those described in the aboveembodiment [1]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-10-2]

Preferably, the compound of the above embodiment [1-10] is a compoundrepresented by the above formula (I-c) wherein the definition of q, Z,R², R³, R⁴, and R⁵ in the formula (I-c) have the same definitions asthose described in the above embodiment [1]; p represents an integer of0 to 4; R¹ each independently represents a halogen atom, a hydroxylgroup, a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₁₋₆alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ group wherein R⁷ andR⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the same definitionsas those described in the above embodiment [1]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-10-2-2]

More preferably, the compound of the above embodiment [1-10] is acompound represented by the above formula (I-c) wherein the definitionof p, Z, R¹, R², R³, R⁴, R⁵, and ring A″ represented by the partialstructural formula (II″) in the formula (I-c) have the same definitionsas those described in the above embodiment [1-10-2]; and q represents aninteger of 0 to 3, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-10-3]

Even more preferably, the compound of the above embodiment [1-10] is acompound represented by the above formula (I-c) wherein the definitionof q, Z, R², R³, R⁴, and R⁵ in the formula (I-c) have the samedefinitions as those described in the above embodiment [1]; p representsan integer of 0 to 3; R¹ each independently represents a halogen atom, ahydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfonyl group, a —CONR^(7A)R^(BA) group, or an —NR^(7A)R^(BA)group wherein R^(7A) and R^(8A) in the —NR^(7A)R^(8A) group and the—CONR^(7A)R^(BA) group have the same definitions as those of R^(7A) andR^(8A) in the above embodiment [1-1-2]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-10-3-2]

Further preferably, the compound of the above embodiment [1-10] is acompound represented by the above formula (I-c) wherein the definitionof p, Z, R¹, R², R³, R⁴, R⁵, and ring A″ represented by the partialstructural formula (II″) in the formula (I-c) have the same definitionsas those described in the above embodiment [1-10-3]; and q represents aninteger of 0 to 2, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

[1-10-4]

Still further preferably, the compound of the above embodiment [1-10] isa compound represented by the above formula (I-c) wherein the definitionof q, Z, R², R³, R⁴, and R⁵ in the formula (I-c) have the samedefinitions as those described in the above embodiment [1]; p representsan integer of 1 to 3; R¹ each independently represents a halogen atom, ahydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, or aC₁₋₆ alkylsulfonyl group; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-10-4-2]

Still further preferably, the compound of the above embodiment [1-10] isa compound represented by the above formula (I-c) wherein the definitionof Z, R¹, R², R³, R⁴, R⁵, and ring A″ represented by the partialstructural formula (II″) in the formula (I-c) have the same definitionsas those described in the above embodiment [1-10-4]; p represents aninteger of 0 to 3; and q represents an integer of 0 or 1, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-10-5]

Particularly preferably, the compound of the above embodiment [1-10] isa compound represented by the above formula (I-c) wherein q, Z, R², R³,R⁴, and R⁵ have the same definitions as those described in the aboveembodiment [1]; p represents an integer of 1 or 2; R¹ each independentlyrepresents a C₁₋₆ alkyl group or a C₁₋₆ alkoxyl group, and morespecifically, R¹ represents a methyl group, a methoxy group, or thelike; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-10-5-2]

More particularly preferably, the compound of the above embodiment[1-10] is a compound represented by the above formula (I-c) wherein thedefinition of Z, R², R³, R⁴, R⁵, R⁵, and ring A″ represented by thepartial structural formula (II″) in the formula (I-c) have the samedefinitions as those described in the above embodiment [1-10-5]; prepresents an integer of 0 to 3; q represents an integer of 0 or 1; R¹each independently represents a halogen atom, a C₁₋₆ alkyl group, acyano group, a halogenated C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl group,and more specifically, R¹ represents fluorine, a cyano group, a methylgroup, a trifluoromethyl group, a methoxy group, or the like, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-10-6]

Even more particularly preferably, the compound of the above embodiment[1-10] is a compound represented by the above formula (I-c) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, and ring A″ in the formula(I-c) have the same definitions as those described in the aboveembodiment [1-10-5-2]; and a specific ring A″ group, in which thedefinitions of the above described p, R¹, and ring A″ are combined,represents a 4-methylpyrimidin-2-yl group, a 3-cyano-pyridin-2-yl group,a 3-methylpyridin-2-yl group, a 4-fluoropyridin-2-yl group, a4-methylpyridin-2-yl group, a 4-methoxy-pyridin-2-yl group, a5-fluoropyridin-2-yl group, a 5-methylpyridin-2-yl group, a6-cyano-pyridin-2-yl group, a 6-methylpyridin-2-yl group, a6-methoxypyridin-2-yl group, a 3,6-dimethylpyrazin-2-yl group, or a6-methylpyrazin-2-yl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-10a]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-c):

wherein the definition of q, Z, R³, R⁴, and R⁵ in the formula (I-c) havethe same definitions as those described in the above embodiment [1]; p,R¹, R⁶, and ring A″ represented by the partial structural formula (II″)have the same definitions as those described in the above embodiment[1-10]; and R² represents a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkylgroup, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-10a-2]

Preferably, the compound of the above embodiment [1-10a] is a compoundrepresented by the above formula (I-c) wherein R³ has the samedefinitions as those described in the above embodiment [1-3]; R⁴ has thesame definitions as those described in the above embodiment [1-4]; Z andR⁵ have the same definitions as those described in the above embodiment[1-5]; q has the same definitions as those described in the aboveembodiment [1-7]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-10-2-2]; and R² represents a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-10a-3]

More preferably, the compound of the above embodiment [1-10a] is acompound represented by the above formula (I-c) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-2]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-2];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-2]; q has the same definitions as those described in theabove embodiment [1-7-2]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-10-3-2]; and R² represents a C₁₋₆ alkyl group ora halogenated C₁₋₆ alkyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-10a-4]

Even more preferably, the compound of the above embodiment [1-10a] is acompound represented by the above formula (I-c) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-3]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-3];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-3]; q has the same definitions as those described in theabove embodiment [1-7-3]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-10-4-2]; and R² represents a C₁₋₆ alkyl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-10a-5]

Particularly preferably, the compound of the above embodiment [1-10a] isa compound represented by the above formula (I-c) wherein R³ has thesame definitions as those described in the above embodiment [1-3-4]; Zand R⁵ have the same definitions as those described in the aboveembodiment [1-5-4]; q has the same definitions as those described in theabove embodiment [1-7-4]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-10-5-2]; R² represents a C₁₋₆ alkyl group, andmore specifically, R² represents a methyl group or the like; and R⁴represents a C₆₋₁₄ aryl group or a 3- to 14-membered non-aromaticheterocyclic group wherein the C₆₋₁₄ aryl group and the 3- to14-membered non-aromatic heterocyclic group, which are represented byR⁴, are each optionally substituted with one or two halogen atoms, andspecifically, R⁴ represents phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,5-difluorophenyl, pyrrolidinyl, 2-fluoropyrrolidinyl,3-fluoropyrrolidinyl, or the like, and R⁴ preferably represents phenyl,3-fluorophenyl, or pyrrolidinyl, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-10a-6]

More particularly preferably, the compound of the above embodiment[1-10a] is a compound represented by the above formula (I-c) wherein p,q, Z, R¹, R², R³, R⁴, R⁵, and ring A″ have the same definitions as thosedescribed in the above embodiment [1-10a-5]; and a specific ring A″group, in which the definitions of the above described p, R¹, and ringA″ are combined, represents a 4-methylpyrimidin-2-yl group, a3-cyano-pyridin-2-yl group, a 3-methylpyridin-2-yl group, a4-fluoropyridin-2-yl group, a 4-methylpyridin-2-yl group, a4-methoxy-pyridin-2-yl group, a 5-fluoropyridin-2-yl group, a5-methylpyridin-2-yl group, a 6-cyano-pyridin-2-yl group, a6-methylpyridin-2-yl group, a 6-methoxypyridin-2-yl group, a3,6-dimethylpyrazin-2-yl group, or a 6-methylpyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-d):

wherein the definition of Z, R², R³, R⁴, and R⁵ in the formula (I-d)have the same definitions as those described in the above embodiment[1]; p represents an integer of 0 to 4; q represents an integer of 0 to3; R¹ each independently represents a halogen atom, a hydroxyl group, anitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group,a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxylgroup, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylcarbonyl group, ahydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfinyl group, aC₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ group whereinR⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the samedefinitions as those described in the above embodiment [1]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-11-2]

Preferably, the compound of the above embodiment [1-11] is a compoundrepresented by the above formula (I-d) wherein the definition of Z, R²,R³, R⁴, and R⁵ in the formula (I-d) have the same definitions as thosedescribed in the above embodiment [1]; p represents an integer of 0 to4; q represents an integer of 0 to 3; R¹ each independently represents ahalogen atom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxylgroup, a C₁₋₆ alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group,a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ group whereinR⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the samedefinitions as those described in the above embodiment [1]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-11-3]

More preferably, the compound of the above embodiment [1-11] is acompound represented by the above formula (I-d) wherein the definitionof Z, R², R³, R⁴, and R⁵ in the formula (I-d) have the same definitionsas those described in the above embodiment [1]; p represents an integerof 0 to 3; q represents an integer of 0 to 2; R¹ each independentlyrepresents a halogen atom, a hydroxyl group, a nitro group, a cyanogroup, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenatedC₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoylgroup, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonyl group, a—CONR^(7A)R^(8A) group, or an —NR^(7A)R^(8A) group wherein R^(7A) andR^(8A) in the —NR^(7A)R^(8A) group and the —CONR^(7A)R^(8A) group havethe same definitions as those of R^(7A) and R^(8A) in the aboveembodiment [1-1-2];

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-11-4]

Even more preferably, the compound of the above embodiment [1-11] is acompound represented by the above formula (I-d) wherein the definitionof Z, R², R³, R⁴, and R⁵ in the formula (I-d) have the same definitionsas those described in the above embodiment [1]; p represents an integerof 1 to 3; q represents an integer of 0 to 2; R¹ each independentlyrepresents a halogen atom, a hydroxyl group, a nitro group, a cyanogroup, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, a halogenatedC₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoylgroup, a C₁₋₆ alkylthio group, or a C₁₋₆ alkylsulfonyl group; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-11-4-2]

Further preferably, the compound of the above embodiment [1-11] is acompound represented by the above formula (I-d) wherein the definitionof Z, R¹, R², R³, R⁴, R⁵, and ring A″ represented by the partialstructural formula (II″) in the formula (I-d) have the same definitionsas those described in the above embodiment [1-11-4]; p represents aninteger of 0 to 3; and q represents an integer of 0 or 1, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11-5]

Particularly preferably, the compound of the above embodiment [1-11] isa compound represented by the above formula (I-d) wherein the definitionof Z, R², R³, R⁴, and R⁵ in the formula (I-d) have the same definitionsas those described in the above embodiment [1]; p represents an integerof 1 to 3; q represents an integer of 0 or 1; R¹ each independentlyrepresents a halogen atom, a cyano group, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl group, and morespecifically, R¹ represents fluorine, chlorine, a cyano group, a methylgroup, a trifluoromethyl group, a methoxy group, or the like;

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-11-5-2]

More particularly preferably, the compound of the above embodiment[1-11] is a compound represented by the above formula (I-d) wherein thedefinition of Z, R¹, R², R³, R⁴, R⁵, and ring A″ represented by thepartial structural formula (II″) in the formula (I-d) have the samedefinitions as those described in the above embodiment [1-11-4]; prepresents an integer of 0 to 3; and q represents an integer of 0 or 1,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11-6]

Even more particularly preferably, the compound of the above embodiment[1-11] is a compound represented by the above formula (I-d) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, and ring A″ in the formula(I-d) have the same definitions as those described in the aboveembodiment [1-11-5-2]; and a specific ring A″ group, in which thedefinitions of the above described p, R¹, and ring A″ are combined,represents a 4,6-dimethylpyrimidin-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 2,5,6-trimethylpyrimidin-4-yl group, a2,5-dimethylpyrimidin-4-yl group, a 2,6-dimethylpyrimidin-4-yl group, a2,6-dimethoxypyrimidin-4-yl group, a 2-methylpyrimidin-4-yl group, a2-methoxypyrimidin-4-yl group, a 5,6-dimethylpyrimidin-4-yl group, a5-chloro-2-methylpyrimidin-4-yl group, a 5-chloropyrimidin-4-yl group, a5-fluoro-2-methylpyrimidin-4-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a5-fluoro-6-methylpyrimidin-4-yl group, a 5-methylpyrimidin-4-yl group, a5-methoxypyrimidin-4-yl group, a 6-methylpyrimidin-4-yl group, a6-methoxy-5-methylpyrimidin-4-yl group, a 4-methylpyridazin-3-yl group,a 5-methylpyridazin-3-yl group, a 6-methylpyridazin-3-yl group, apyridazin-3-yl group, a 3-cyanopyridin-2-yl group, a3-methoxypyridin-2-yl group, a 4,6-dimethylpyridin-2-yl group, a4-fluoropyridin-2-yl group, a 4-methylpyridin-2-yl group, a4-methoxypyridin-2-yl group, a 5-cyanopyridin-2-yl group, a5-fluoropyridin-2-yl group, a 5-methylpyridin-2-yl group, a6-(trifluoromethyl)pyridin-2-yl group, a 6-methylpyridin-2-yl group, a3,6-dimethyl-pyrazin-2-yl group, a 3-methylpyrazin-2-yl group, a3-methoxypyrazin-2-yl group, a 5-methylpyrazin-2-yl group, a6-methylpyrazin-2-yl group, or a 6-methoxypyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11a]

The compound of the above embodiment [1] represented by the aboveformula (I) is preferably a compound represented by the followingformula (I-d):

wherein the definition of q, Z, R³, R⁴, and R⁵ in the formula (I-d) havethe same definitions as those described in the above embodiment [1]; p,R¹, R⁶, and ring A″ represented by the partial structural formula (II″)have the same definitions as those described in the above embodiment[1-11]; and R² represents a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkylgroup, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.[1-11a-2]

Preferably, the compound of the above embodiment [1-11a] is a compoundrepresented by the above formula (I-d) wherein R³ has the samedefinitions as those described in the above embodiment [1-3]; R⁴ has thesame definitions as those described in the above embodiment [1-4]; Z andR⁵ have the same definitions as those described in the above embodiment[1-5]; q has the same definitions as those described in the aboveembodiment [1-7]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-11-2]; and R² represents a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11a-3]

More preferably, the compound of the above embodiment [1-11a] is acompound represented by the above formula (I-d) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-2]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-2];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-2]; q has the same definitions as those described in theabove embodiment [1-7-2]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-11-3]; and R² represents a C₁₋₆ alkyl group or ahalogenated C₁₋₆ alkyl group, or a pharmaceutically acceptable saltthereof, or a solvate thereof.

[1-11a-4]

Even more preferably, the compound of the above embodiment [1-11a] is acompound represented by the above formula (I-d) wherein R³ has the samedefinitions as those described in the above embodiment [1-3-3]; R⁴ hasthe same definitions as those described in the above embodiment [1-4-3];Z and R⁵ have the same definitions as those described in the aboveembodiment [1-5-3]; q has the same definitions as those described in theabove embodiment [1-7-3]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-11-4-2]; and R² represents a C₁₋₆ alkyl group,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11a-5]

Particularly preferably, the compound of the above embodiment [1-11a] isa compound represented by the above formula (I-d) wherein R³ has thesame definitions as those described in the above embodiment [1-3-4]; Zand R⁵ have the same definitions as those described in the aboveembodiment [1-5-4]; q has the same definitions as those described in theabove embodiment [1-7-4]; p, R¹, and ring A″ represented by the partialstructural formula (II″) have the same definitions as those described inthe above embodiment [1-11-5-2]; R² represents a C₁₋₆ alkyl group, andmore specifically, R² represents a methyl group or the like; and R⁴represents a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromaticheterocyclic group, or a 5- to 7-membered monocyclic heteroaryl groupwherein the C₆₋₁₄ aryl group, the 3- to 14-membered non-aromaticheterocyclic group, and the 5- to 7-membered monocyclic heteroarylgroup, which are represented by R⁴, are each optionally substituted withone or two halogen atoms, C₁₋₆ alkyl groups, or halogenated C₁₋₆ alkylgroups, and specifically, R⁴ represents phenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2,5-dimethylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, pyrrolidinyl,2-fluoropyrrolidinyl, 3-fluoropyrrolidinyl, 2-methylpyrrolidinyl,3-methylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl,3-trifluoromethylpyrrolidinyl, 2-pyridinyl, 3-pyridinyl, 2-pyridinyl, orthe like, and R⁴ preferably represents phenyl, 2-methylphenyl,4-fluorophenyl, pyrrolidinyl, 2-methylpyrrolidinyl,3-fluoropyrrolidinyl, 2-trifluoromethylpyrrolidinyl, or 3-pyridinyl, ora pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-11a-6]

More particularly preferably, the compound of the above embodiment[1-11a] is a compound represented by the above formula (I-d) wherein thedefinition of p, q, Z, R¹, R², R³, R⁴, R⁵, and ring A″ in the formula(I-d) have the same definitions as those described in the aboveembodiment [1-11a-5]; and a specific ring A″ group, in which thedefinitions of the above described p, R¹, and ring A″ are combined,represents a 4,6-dimethylpyrimidin-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 2,5,6-trimethylpyrimidin-4-yl group, a2,5-dimethylpyrimidin-4-yl group, a 2,6-dimethylpyrimidin-4-yl group, a2,6-dimethoxypyrimidin-4-yl group, a 2-methylpyrimidin-4-yl group, a2-methoxypyrimidin-4-yl group, a 5,6-dimethylpyrimidin-4-yl group, a5-chloro-2-methylpyrimidin-4-yl group, a 5-chloropyrimidin-4-yl group, a5-fluoro-2-methylpyrimidin-4-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a5-fluoro-6-methylpyrimidin-4-yl group, a 5-methylpyrimidin-4-yl group, a5-methoxypyrimidin-4-yl group, a 6-methylpyrimidin-4-yl group, a6-methoxy-5-methylpyrimidin-4-yl group, a 4-methylpyridazin-3-yl group,a 5-methylpyridazin-3-yl group, a 6-methylpyridazin-3-yl group, apyridazin-3-yl group, a 3-cyanopyridin-2-yl group, a3-methoxypyridin-2-yl group, a 4,6-dimethylpyridin-2-yl group, a4-fluoropyridin-2-yl group, a 4-methylpyridin-2-yl group, a4-methoxypyridin-2-yl group, a 5-cyanopyridin-2-yl group, a5-fluoropyridin-2-yl group, a 5-methylpyridin-2-yl group, a6-(trifluoromethyl)pyridin-2-yl group, a 6-methylpyridin-2-yl group, a3,6-dimethyl-pyrazin-2-yl group, a 3-methylpyrazin-2-yl group, a3-methoxypyrazin-2-yl group, a 5-methylpyrazin-2-yl group, a6-methylpyrazin-2-yl group, or a 6-methoxypyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[1-12]

As described above, the embodiments [1-1] to [1-11a-6] of the presentinvention, the preferred embodiments thereof, and further, definitionsof substituents are appropriately combined, so that preferredembodiments of the compound of the above embodiment [1] represented bythe above formula (I) can be arbitrarily formed.

[2]

A second embodiment of the present invention is illustrated, by way ofexample, with the below-listed compounds that are preferable as thecompounds of the above embodiment [1] represented by the above formula(I), or pharmaceutically acceptable salts thereof, or their solvates, ortheir optical isomers. It is to be noted that the following compoundnames are based on English names obtained in accordance with thechemical nomenclature program of Cambridge Soft Chem BioDraw Ultra12.0.2.1076.

TABLE 1-1 Compound name Example No.1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenylimidazo[1,2- 1.1a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenylimidazo[1,2- 1.2a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl- 1.3imidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5- carboxamide4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl- 1.4N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole- 5-carboxamide1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)- 1.54-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5- carboxamide1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)- 1.64-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5- carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2- 1.7phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5- carboxamide1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8- 2.1tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5- carboxamide

TABLE 1-2 Compound name Example No.4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8- 2.2tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5- carboxamide1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2- 2.3a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl- 2.45,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H- pyrazole-5-carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N- 2.5(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N- 2.6(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(3-fluoro- 2.7phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-lH-pyrazole-5-carboxamideN-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2- 2.8a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

TABLE 1-3 Compound name Example No.1-methyl-4-(6-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo2.9  [1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(2-phenyl-5,6,7,8- 2.10tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(6-methoxypyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8- 2.11tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(2-methylthiazol-4-yl)-N-(2-phenyl-5,6,7,8- 2.12tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-phenyl-5,6,7,8- 2.13tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(3-isopropy1-1,2,4-thiadiazol-5-yl)-1-methyl-N-(2-phenyl-5,6,7,8- 2.14tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(5-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8- 2.15tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

TABLE 1-4 Compound name Example No.1-methyl-4-(4-methylpyrimidin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo2.16 [1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(1-methyl-1H-imidazol-4-yl)-N-(2-phenyl-5,6,7,8- 2.17tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideN-(2-(2,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-2.18yl)-1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxamideN-(3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-2.19methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8- 2.20tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo2.21 [1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(4-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo2.22 [1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

TABLE 1-5 Compound name Example No.N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-2.23 1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxamideN-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-2.24 1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)- 2.254-(thiazol-4-yl)-1H-pyrazole-5-carboxamide1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)- 2.264-(thiazol-2-yl)-1H-pyrazole-5-carboxamide4-(4-(tert-butyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8- 2.27tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8- 2.28tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-2.291-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

TABLE 1-6 Compound name Example No.N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4- 3.1(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4- 3.2(5-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4- 3.3(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4- 3.4fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4- 3.5(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4- 3.6(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3- 3.7methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-7 Example Compound name No.N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4- 3.8(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazol[1,5-a]pyridin-7-yl)-1-methyl- 3.94-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl- 3.104-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]- 3.11[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-N-(6-fluoro-2-phenyl- 3.12[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5- carboxamide4-(3-cyanopyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo 3.13[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(3,6-dimethyl-pyrazin-2-yl)-N-(6-fluoro-2-phenyl- 3.14[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5- carboxamide

TABLE 1-8 Compound name Example No.4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]3.15 pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(2-methoxyphenyl)-[1,2,4]triazolo3.16 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]3.17 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(4-ethylthiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-3.18 yl)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)-3.19[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methy1-1H-pyrazole-5-carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl- 3.20[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideN-(5-chloro-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3.21 4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-9 Compound name Example No.4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]3.22 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(5-cyanopyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-3.23 7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.24 (4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.25 (2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2-methoxypyrimidin-3.26 4-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo3.27 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-methoxypyrazin-3.28 2-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-10 Compound name Example No.4-(5-chloropyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]3.29 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(2,6-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]3.30 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-methoxy-3.31 5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.32 (3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.33 (5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5- 3.34methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(5,6-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]3.35 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-11 Compound name Example No.4-(5-fluoro-2-methylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo3.36 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.37 (2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-fluoro-6-3.38 methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.39 (6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide4-(2,6-dimethoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo3.40 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(5-chloro-2-methylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo3.41 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-methoxypyrazin-3.42 2-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-12 Compound name Example No.N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.43 (4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxamide4-(4,6-dimethylpyrimidin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]3.44 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.45 (6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.46 (5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.47 (pyridazin-3-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.48 (1-methyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-(pyridin-3-yl)-[1,2,4]triazolo3.49 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-13 Compound name Example No.4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-(o-tolyl)-[1,2,4]triazolo[1,5-a]3.50 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-3.51 (5-methylpyridin-2-yl)-1H-pyrazole-5-carboxamideN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-methoxypyridin-3.52 2-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]3.53 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]3.54 pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(S)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-4.1  1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(S)-4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(2- 4.2 methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

TABLE 1-14 Compound name Example No.(S)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-4.3 7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide(S)-1-methyl-4-(4-methylpyridin-2-yl)-N-(2-(2-methylpyrrolidin-1-yl)-4.4 [1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(S)-4-(4-methoxypyridin-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-4.5 [1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(S)-1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-(2-methylpyrrolidin-1- 4.6yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(S)-1-methyl-4-(6-methylpyridin-2-yl)-N-(2-(2-methylpyrrolidin-1-yl)-4.7 [1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(S)-4-(4,6-dimethylpyridin-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-4.8 yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(S)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-(2- 4.9methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

TABLE 1-15 Compound name Example No.(S)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4.10 4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(R)-N-(6-fluoro-2-(2trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]4.11pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide(R)-4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]4.12 triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(R)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-4.13 (4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(R)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-4.14[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(S)-4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]4.15 triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(S)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-4.16 (6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide

TABLE 1-16 Compound name Example No.(S)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-4.17 (4-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide(S)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4.18 4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(S)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-4.19 (6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide(S)-4-(4,6-dimethylpyridin-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo4.20 [1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(S)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-4.21 (6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide(S)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-4.22 (4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(S)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-4.23[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-17 Compound name Example No.(S)-4-(4,6dimethylpyridin-2-yl)-N-(6-fluoro-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]4.24 triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]4.25 triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-4.26 [1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-4.27 (6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide4-(4-methoxypyridin-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]4.28 pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]4.29 pyridin-7-yl)-1H-pyrazole-5-carboxamide1-methyl-4-(4-methylpyridin-2-yl)-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]4.30 pyridin-7-yl)-1H-pyrazole-5-carboxamide

TABLE 1-18 Example Compound name No.1-methyl-4-(6-methylpyridin-2-y1)-N-(2-(pyrrolidin-1-y1)- 4.31[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4,6-dimethylpyridin-2-y1)-1-methyl-N-(2-(pyrrolidin-1-y1)- 4.32[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-methylthiazol-2-y1)-1-methyl-N-(2- 4.33(pyrrolidin-1-y1)-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide1-methyl-N-(2-(pyrrolindin-1-y1)-[1,2,4]triazolo[1,5-a]pyridin-7- 4.34y1)-4-(4-(trifluoromethyl)thiazol-2-y1)-1H-pyrazole-5- carboxamide4-(2,5-dimethylpyrimidin-4-y1)-N-(6-fluoro-2-(pyrrolidin-1-y1)- 4.35[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5- carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-y1)-N-(2-((2S,6R)-2,6- 4.36dimethylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-methylthiazol-2-y1)-1-methyl-N- 5.1(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide

TABLE 1-19 Example Compound name No.4-(4-(difluoromethyl)thiazol-2-y1)-N-(2-(4-fluorophenyl)- 5.25,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-y1)-N-(2- 5.3(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5- carboxamide4-(4,5-dimethylthiazol-2-y1)-1-methyl-N-(2-phenyl-5,6,7,8- 5.4tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-vinylthiazol-2-y1)-1-methyl-N- 5.5(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-ethylthiazol-2-y1)-1-methyl-N- 5.6(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(5-bromo-4-methylthiazol-2-y1)-1-methyl-N-(2-phenyl- 5.75,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(5-cycloprophyl-4-(diflyoromethyl)thiazol-2-y1)-1- 5.8methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5- carboxamide

TABLE 1-20 Example Compound name No.1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a] 5.9pyridin-7-y1)-4-(4trifluoromethyl)thiazol-2-y1)-1H-pyrazole-5-carboxamide4-(4-cyanothiazol-2-y1)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro- 5.10[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(5-(2-ethoxyethyl)-4-methylthiazol-2-y1)-1-methyl-N-(2-phenyl- 5.115,6,7,8-thtrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(5-ethyl-1,3,4-thiadiazol-2-y1)-1-methyl-N-(2-phenyl-5,6,7,8- 5.12tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamine4-(5-bromo-2-methylthiazol-4-y1)-1-methyl-N-(2-phenyl-5,6,7,8- 5.13tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 4-(3,6-dimethylpyrazin-2-y1)-1-methyl-N-(2-phenyl-5,6,7,8-5.14 tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-y1)-N-(2-phenyl-5,6,7,8- 5.15tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide

TABLE 1-21 Example Compound name No.4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-((R)-2- 5.16(methoxymethyl)pyrrolidin-l-y1)-5,6,7,8-tetrahydro-[1,2,4[triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H- pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-y1)-1-methyl-N- 5.17(2-pheny1-5,6,7,8-tetrahydro-[1,2,4[triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide1-methyl-4-(4-methylthiazol-2-y1)-N-(2-phenyl-5,6,7,8- 5.18tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide1-methyl-4-(6-methylpyridin-2-y1)-N-(2-phenyl-5,6,7,8- 5.19tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 1-methyl-4-(4-methylpyridin-2-y1)-N-(2-phenyl-5.20 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 1-methyl-N-(2-pheny1-5,6,7,8-tetrahydro- 5.21[1,2,4]triazolo[1,5-a]pyridin-7-y1)-4-(6-(trifluoromethyl)pyridin-2-y1)-1H-pyrazole-5- carboxamide1-methyl-4-(3-methylpyridin-2-y1)-N-(2-phenyl-5,6,7,8- 5.22tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide

TABLE 1-22 Example Compound name No.4-(4-fluoropyridin-2-y1)-1-methyl-N-(2-phenyl-5,6,7,8- 5.23tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 4-(5-fluoropyridin-2-y1)-1-methyl-N-(2-phenyl-5.24 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4-methoxypyridin-2-y1)-1-methyl-N-(2-phenyl- 5.255,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 1-methyl-4-(5-methylpyridin-2-y1)-N-(2-phenyl-5.26 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 4-(3-cyanopyridin-2-y1)-1-methyl-N-(2-phenyl-5.27 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(2,5-dimethylthiazol-4-y1)-N-(2-(4-fluorophenyl)-5,6,7,8- 5.28tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(5-chloro-4-(difluoromethyl)thiazol-2-y1)-1-methyl-N- 5.29(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide

TABLE 1-23 Example Compound name No.4-(5-acetyl-2-methylthiazol-4-y1)-1-methyl-N-(2-phenyl-5,6,7,8- 5.30tetrahydro-[1,2,4]triazole[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 4-(5-(1-hydroxyethyl)-2-methylthiazol-4-y1)-1-methyl-N- 5.31(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-y1)-N-(2-(2-fluorophenyl)-5,6,7,8- 5.32tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-y1)-N-(2-(3-fluorophenyl)-5,6,7,8- 5.33tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)thiazol-2-y1)-N-(2-(2-methoxyphenyl)- 5.345,6,7,8-tetrahydro-[1,2,4]trizolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-y1)-N-(2-(4- 5.35fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(4-(difluoromethyl)-5-methylthiazol-2-y1)-N-(2- 5.36(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]trizolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide

TABLE 1-24 Example Compound name No.4-(5-chloro-4-(difluoromethyl)thiazol-2-y1)-N-(2- 5.37(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(5-cyclopropyl-4-methylthiazol-2-y1)-1-methyl-N- 5.38(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(2,5-dimethylthiazol-4-y1)-1-methyl-N-(2-phenyl- 5.395,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide 4-(6-cyanopyridin-2-y1)-1-methyl-N-(2-phenyl-5.40 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide4-(4-cyanothiazol-2-y1)-N-(2-(4-fluorophenyl)-5,6,7,8- 5.41tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-y1)-N-(2-(3- 5.42fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(5-cyclopropyl-4-methylthiazol-2-y1)-N-(2-(4- 5.43fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5- carboxamide

TABLE 1-25 Example Compound name No.4-(5-acetyl-2-methylthiazol-4-y1)-N-(2-(3-fluorophenyl)-5,6,7,8- 5.44tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1-methyl-1H-pyrazole-5-carboxamide4-(4,5-dimethylthiazol-2-y1)-1-methyl-N-(2-(pyrrolidin-1-y1)- 5.455,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide1-methyl-N-(2-(pyrrolidin-l-y1)-5,6,7,8-tetrahydro- 5.46[1,2,4]triazolo[1,5-a]pyridin-7-y1)-4-(4trifluoromethyl)thiazol-2-y1)-1H-pyrazole-5-carboxamide1-methyl-4-(6-methylpyridin-2-y1)-N-(2-(pyrrolidin-l-y1)- 5.475,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-y1)-1H-pyrazole-5-carboxamide

In the compound of the above formula (I), the amide bond is a bond thatmay be converted to an imide acid bond by proton tautomeric isomerism,and the generated tautomeric isomer is included in the above formula(I). The abundance ratio of these structures may change, depending onthe state of the compound represented by the formula (I), namely, asolid state, or a state in which the compound is dissolved in a liquid.

The description regarding any given specific tautomeric isomer in anygiven structural formula in the present specification is not intended tolimit a tautomeric isomer to the any given specific tautomeric isomer,but it is intended to mean that the any given specific tautomeric isomeris a representative of the entire set of tautomeric isomers.

Specifically, if the compound of Example 1.1, for example, has acompound name“1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide,”its tautomeric isomer,1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carbimidicacid (which is not distinguished in terms of E form and Z form) is alsoincluded in the compound of Example 1.1.

In the present specification, unless otherwise specified, when a cyclicgroup is substituted with a variable substituent, it means that thevariable substituent does not bind to a specific carbon atom of thecyclic group or to a specific NH group in the cyclic group. For example,it means that the variable substituent R^(x) in the following formula Acan be substituted with any of carbon atoms i, ii, iii and iv in theformula A; the variable substituent R^(y) in the following formula B canbe substituted on any of carbon atoms v and vi in the formula B; and thevariable substituent R^(z) in the following formula C can be substitutedon any of carbon atoms vii, viii, ix, and x in the formula C.

[3] A third embodiment of the present invention is a pharmaceuticalcomposition comprising, as an active ingredient, at least one of thecompound represented by the above formula (I), a pharmaceuticallyacceptable salt thereof, and a solvate thereof.[4] A fourth embodiment of the present invention is a pharmaceuticalcomposition for treating at least one disease or condition selected fromthe group consisting of certain types of mental disorders andconditions, such as mental disorder, paranoid disorder, and drug-inducedpsychosis, anxiety disorders such as panic disorder andobsessive-compulsive disorder, motor disorders including Parkinson'sdisease and Huntington's disease, mood disorder, neurodegenerativedisorder, disorder involving deficits in attention and/or cognition,obesity, and drug addiction, wherein the pharmaceutical compositioncomprises, as an active ingredient, at least one of the compoundrepresented by the above formula (I), a pharmaceutically acceptable saltthereof, and a solvate thereof, in an effective amount for treating thedisease or condition.

Examples of the “mental disorders and conditions” that can be treatedaccording to the present invention include (1) paranoid, disorganized,catatonic, undifferentiated, or residual schizophrenia, (2)schizophreniform disorder, (3) paranoid or depressive schizoaffectivedisorder, (4) paranoid disorder, (5) substance-induced mental disorder,for example, psychosis induced by alcohol, amphetamine, cannabis,cocaine, a hallucinatory drug, an inhalant, opioid, or phencyclidine,(6) paranoic personality disorder, and (7) schizotypal personalitydisorder. However, the mental disorders and conditions are not limitedthereto.

In the present specification, unless otherwise specified, examples ofthe symptoms of “schizophrenia and schizophreniform disorder” include(1) positive symptom, negative symptom, and delusional and/orhallucinogenic symptom associated therewith, (2) disorganized speech(frequent off-topic or incoherent speech), (3) flattening of emotion (asignificant reduction in the width and strength of emotionalexpression), (4) alogia (a reduction in content and amount of speech),(5) anhedonia (the disappearance/diminution of ability to experiencepleasure), (6) inappropriate affect, (7) dysphoria (e.g. depression,anxiety, and anger), (8) loss of motivation, (9) unsocial personality(loss of capacity of obtaining pleasure from social interaction), and(10) a part of cognitive function disorder. However, the schizophreniaand schizophreniform disorder are not limited thereto.

Examples of the “motor disorders” that can be treated according to thepresent invention include (1) Huntington's disease and dyskinesiaassociated with dopamine agonist therapy, (2) Parkinson's disease, (3)restless legs syndrome (RLS), and (4) essential tremor. However, themotor disorders are not limited thereto.

Examples of the “other disorders” that can be treated according to thepresent invention include (1) obsessive-compulsive disorder, (2)Tourette's syndrome, and (3) tic disorder. However, the other disordersare not limited thereto.

Examples of the “anxiety disorders” that can be treated according to thepresent invention include (1) panic disorder, (2) agoraphobia, (3)specific phobias, (4) social phobias, (5) obsessive-compulsive disorder,(6) posttraumatic stress disorder, (7) acute stress disorder, and (8)generalized anxiety disorder. However, the anxiety disorders are notlimited thereto.

In the present specification, unless otherwise specified, the term “drugaddiction” means abnormal desire for drugs. In general, the drugaddiction has characteristics including motivational disorder such ascompulsion to take a desired drug, and an episode of strong desire fordrugs. Examples of the drug addiction include alcohol, amphetamine,cocaine, and opium addiction.

In the present specification, unless otherwise specified, the term“deficits in attention and/or cognition” in the context of “disorderinvolving deficits in attention and/or cognition” means that one or morecognitive functions in a specific individual, such as memory,intellectual, learning, and logical capacity, are below normal level incomparison with other individuals of the same age. Moreover, the term“deficits in attention and/or cognition” means a reduction in thefunctions of any given specific individual, in terms of one or morecognitive aspects, for example, caused by age-related cognitive decline.

Examples of the “disorder involving deficits in attention and/orcognition” that can be treated according to the present inventioninclude (1) dementia, such as Alzheimer's disease, multiple cerebralinfarction, alcoholic dementia or other drug-related dementia, dementiaassociated with intracranial tumor or brain damage, dementia associatedwith Huntington's disease or Parkinson's disease, or AIDS-relateddementia, (2) delirium, (3) amnestic disorder, (4) posttraumatic stressdisorder (PTSD), (5) mental retardation, (6) learning disorder, such asdyslexia, mathematics disorder, or disorder of written expression, (7)attention-deficit hyperactivity disorder (ADHA), and (8) age-relatedcognitive decline. However, the disorder involving deficits in attentionand/or cognition are not limited thereto.

Examples of the “mood disorder” and the “mood episode” that can betreated according to the present invention include (1) major depressiveepisode (mild level, middle level, or severe level type), manic episode,mixed affective episode, and hypomanic episode, (2) atypical depression,(3) melancholic depression, (4) catatonic depression, (5) postpartummood episode, (6) postapoplectic depression, (7) major depressivedisorder, (8) dysthymic disorder/dysthymia, (9) minor depressivedisorder, (10) premenstrual dysphoric disorder, (12) postschizophrenicdepressive disorder, (13) major depressive disorder occurring withparanoid disorder or mental disorder such as schizophrenia, (14) bipolardisorder, such as bipolar disorder type I and bipolar disorder type II,and (15) cyclothymic disorder. However, the mood disorder and the moodepisode are not limited thereto.

In the present specification, unless otherwise specified, the term“neurodegenerative disorder or condition” means nervous functiondisorder or condition, which is caused by neuronal dysfunction and/orneuronal death in the central nerve system. Examples of the treatmentfor the aforementioned disorder and condition include administration ofa drug for enhancing the function of damaged or normally workingneurons, so as to prevent neuronal dysfunction and/or neuronal deaththat are under critical conditions, and/or to compensate the loss offunction caused by such neuronal dysfunction or neuronal death that isunder critical conditions, in the aforementioned disorder or condition.

Examples of the “neurodegenerative disorder and condition” that can betreated according to the present invention include (1) Parkinson'sdisease, (2) Huntington's disease, (3) dementia, such as Alzheimer'sdisease, multi-infarct dementia, AIDS-related dementia, andfrontotemporal dementia, (4) neurodegeneration associated with braindamage, (5) neurodegeneration associated with stroke, andneurodegeneration associated with cerebral infarction, (6)hypoglycemia-induced neurodegeneration, (7) neurodegeneration associatedwith epileptic seizure, (8) neurodegeneration associated with neurotoxicaddiction, (9) multiple system atrophy, and (10) neurodegeneration ofstriatal medium-sized spiny neurons. However, the neurodegenerativedisorder and condition are not limited thereto.

In the present specification, unless otherwise specified, the term“neurotoxic addiction” indicates intoxication by neurotoxin. Neurotoxinis any given chemical substance or substance that may cause neuraldeath, namely, neurological damage. Examples of the neurotoxin includealcohol. When a pregnant woman abuses alcohol, her newborn child wouldsuffer from alcoholic intoxication and neurological damage, which areconsidered to be fetal alcohol syndrome. Other examples of theneurotoxin include kainic acid, domoic acid, acromelic acid, certaintypes of agricultural chemicals (e.g. dichloro diphenyl trichloroethane(DDT)), certain types of insecticides (e.g. organophosphorus acids),volatile organic solvents (e.g. toluene), metals (e.g. lead, mercury,arsenic, phosphorus, and aluminum), certain types of chemical substancesused as weapons (e.g. Agent Orange that is a defoliant, and nerve gas),and neurotoxic anti-tumor agents. However, the neurotoxin is not limitedthereto.

In the present specification, unless otherwise specified, the term“treat” used in the context of the phrase “treat the disease orcondition” means to recover, alleviate, or suppress progression of the“disease or condition” or one or more “diseases or conditions.” Inaddition, in the present specification, the term “treat” also includes,depending on conditions of patients, prevention of “disease orcondition” which includes prevention of the onset of the “disease orcondition” or the onset of any given symptoms associated therewith, andreduction of the severity of “disease or condition” or the any givensymptoms associated therewith before the onset. In the presentspecification, the term “treat” includes to prevent and improve therecurrence of a certain “disease or condition.”

[5] A fifth embodiment of the present invention is a pharmaceuticalcomposition for treating at least one disease or condition selected fromthe group consisting of certain types of mental disorders andconditions, such as mental disorder, paranoid disorder, and drug-inducedpsychosis, anxiety disorders such as panic disorder andobsessive-compulsive disorder, motor disorders including Parkinson'sdisease and Huntington's disease, mood disorder, neurodegenerativedisorder, disorder involving deficits in attention and/or cognition,obesity, and drug addiction, wherein the pharmaceutical compositioncomprises, as an active ingredient, at least one of the compoundrepresented by the above formula (I), a pharmaceutically acceptable saltthereof, and a solvate thereof, in an effective amount for inhibitingPDE10.[6] A sixth embodiment of the present invention is an agent forpreventing and/or treating at least one disease or condition selectedfrom the group consisting of certain types of mental disorders andconditions such as mental disorder, paranoid disorder, and drug-inducedpsychosis, anxiety disorders such as panic disorder andobsessive-compulsive disorder, motor disorders including Parkinson'sdisease and Huntington's disease, mood disorder, neurodegenerativedisorder, disorder involving deficits in attention and/or cognition,obesity, and drug addiction, wherein the agent comprises, as an activeingredient, at least one of the compound represented by the aboveformula (I), a pharmaceutically acceptable salt thereof, and a solvatethereof.[7] A seventh embodiment of the present invention is an agent fortreating at least one disease or condition selected from the groupconsisting of certain types of mental disorders and conditions such asmental disorder, paranoid disorder and drug-induced mental psychosis,anxiety disorders such as panic disorder and obsessive-compulsivedisorder, motor disorders including Parkinson's disease and Huntington'sdisease, mood disorder, neurodegenerative disorder, disorder involvingdeficits in attention and/or cognition, obesity, and drug addiction,wherein the agent comprises, as an active ingredient, at least one ofthe compound represented by the above formula (I), a pharmaceuticallyacceptable salt thereof, and a solvate thereof.[8] An eighth embodiment of the present invention is an agent forpreventing and/or treating diseases related to a PDE10 receptor, whereinthe agent comprises, as an active ingredient, at least one of thecompound represented by the above formula (I), a pharmaceuticallyacceptable salt thereof, and a solvate thereof.[9] A ninth embodiment of the present invention is an agent for treatingdiseases related to a PDE10 receptor, wherein the agent comprises, as anactive ingredient, at least one of the compound represented by the aboveformula (I), a pharmaceutically acceptable salt thereof, and a solvatethereof.[10] A tenth embodiment of the present invention is a PDE10 inhibitorconsisting of one or more of the compound represented by the aboveformula (I), a pharmaceutically acceptable salt thereof, and a solvatethereof.[11] An eleventh embodiment of the present invention is use of at leastone of the compound represented by the above formula (I), apharmaceutically acceptable salt thereof, and a solvate thereof, as apharmaceutical composition.[11a] An 11a-th embodiment of the present invention is use of at leastone of the compound represented by the above formula (I), apharmaceutically acceptable salt thereof, and a solvate thereof, in theproduction of a pharmaceutical composition.[12] A twelfth embodiment of the present invention is use of at leastone of the compound represented by the above formula (I), apharmaceutically acceptable salt thereof, and a solvate thereof, as aPDE10 inhibitor.[13] A thirteenth embodiment of the present invention is a method fortreating at least one disease or condition selected from the groupconsisting of certain types of mental disorders and conditions such asmental disorder, paranoid disorder and drug-induced psychosis, anxietydisorders such as panic disorder and obsessive-compulsive disorder,motor disorders including Parkinson's disease and Huntington's disease,mood disorder, neurodegenerative disorder, disorder involving deficitsin attention and/or cognition, obesity, and drug addiction, wherein themethod comprises administering at least one of the compound representedby the above formula (I), a pharmaceutically acceptable salt thereof,and a solvate thereof, in an effective amount for treating the diseaseor condition, to a subject in need of treatment for the disease orcondition.[14] A fourteenth embodiment of the present invention is a method fortreating at least one disease or condition selected from the groupconsisting of certain types of mental disorders and conditions such asmental disorder, paranoid disorder and drug-induced psychosis, anxietydisorders such as panic disorder and obsessive-compulsive disorder,motor disorders including Parkinson's disease and Huntington's disease,mood disorder, neurodegenerative disorder, disorder involving deficitsin attention and/or cognition, obesity, and drug addiction, wherein themethod comprises administering at least one of the compound representedby the above formula (I), a pharmaceutically acceptable salt thereof,and a solvate thereof, in an effective amount for inhibiting PDE10, to asubject in need of treatment for the disease or condition.[15] A fifteenth embodiment of the present invention is thepharmaceutical composition according to the embodiment [3] or the methodaccording to the embodiment [13], wherein the disease or condition is atleast one disease or condition selected from the group consisting of (1)paranoid, disorganized, catatonic, undifferentiated, or residualschizophrenia, (2) schizophreniform disorder, (3) paranoid or depressiveschizoaffective disorder, (4) paranoid disorder, (5) substance-inducedmental disorder, (6) psychosis induced by alcohol, amphetamine,cannabis, cocaine, a hallucinatory drug, an inhalant, opioid, orphencyclidine, (7) paranoic personality disorder, (8) schizotypalpersonality disorder, (9) Huntington's disease, (10) dyskinesiaassociated with dopamine agonist therapy, (11) Parkinson's disease, (12)restless legs syndrome, (13) essential tremor, (14) obsessive-compulsivedisorder, (15) Tourette's syndrome, (16) tic disorder, (17) panicdisorder, (18) agoraphobia, (19) specific phobias, (20) social phobias,(21) posttraumatic stress disorder, (22) acute stress disorder, (23)generalized anxiety disorder, (24) dementia; Alzheimer's disease,multiple cerebral infarction, alcoholic dementia or other drug-relateddementia, dementia associated with intracranial tumor or brain damage,dementia associated with Huntington's disease or Parkinson's disease,AIDS-related dementia, or frontotemporal dementia, (25) delirium, (26)amnestic disorder, (27) mental retardation, (28) learning disorder;dyslexia, mathematics disorder, or disorder of written expression, (29)attention-deficit hyperactivity disorder, (30) age-related cognitivedecline, (31) major depressive episode (mild level, middle level, orsevere level type), manic episode, mixed affective episode, or hypomanicepisode, (32) atypical depression, (33) melancholic depression, (34)catatonic depression, (35) postpartum mood episode, (36) postapoplecticdepression, (37) major depressive disorder, (38) dysthymicdisorder/dysthymia, (39) minor depressive disorder, (40) premenstrualdysphoric disorder, (41) postschizophrenic depressive disorder, (42)major depressive disorder occurring with paranoid disorder or mentaldisorder such as schizophrenia, (43) bipolar disorder; bipolar disordertype I and bipolar disorder type II, (44) cyclothymic disorder, (45)neurodegeneration associated with brain damage, (46) neurodegenerationassociated with stroke, or neurodegeneration associated with cerebralinfarction, (47) hypoglycemia-induced neurodegeneration, (48)neurodegeneration associated with epileptic seizure, (49)neurodegeneration associated with neurotoxic addiction, (50) multiplesystem atrophy, and (51) neurodegeneration of striatal medium-sizedspiny neurons.

In each of the aforementioned embodiments [1] to [15] of the presentinvention, when PDE10 inhibitory effect is measured by an appropriatelyselected method, for example, when it is measured in the after-mentionedPharmacological Experiment Example 1 (human-derived PDE10 inhibitoryeffect), it is preferable to use a compound having an IC₅₀ value ofpreferably 100 nM or less, more preferably 50 nM or less, even morepreferably 10 nM or less, further preferably 5.0 nM or less, andparticularly preferably 1.0 nM or less.

In Pharmacological Experiment Example 1 (human PDE10 inhibitory effect),the compound represented by the formula (I) of the present invention, ora pharmaceutically acceptable salt thereof, or a solvate thereof has anexcellent PDE10 inhibitory activity. Moreover, the compound representedby the formula (I) of the present invention, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof is extremely selective toPDE10, and thus, is a selective PDE10 inhibitor.

In the present specification, unless otherwise specified, the term“selective PDE10 inhibitor” means a compound having a significantinhibitory activity on PDE10, rather than on PDEs 1 to 9 or PDE11.

In one embodiment, the “selective PDE10 inhibitor” is preferably acompound having an inhibitory activity on PDE10, which is approximately1/1000 or less of the IC₅₀ values of the compound to inhibit any otherPDE enzymes (e.g. PDE 1A, 2A, 3A, 4A, 4B, 5A, 6, 7A, 7B, 8A, 9A, and11A). (In other word, this compound inhibits the activity of PDE10 at anIC₅₀ value that is approximately 1/1000 or less of its IC₅₀ valuesnecessary for inhibition of any other PDE enzymes.)

In the present specification, unless otherwise specified, when the term“the compound of the formula (I),” “the compound represented by theformula (I),” or the like is used, it also refers to “the compound ofthe formula (I-a),” “the compound of the formula (I-b),” “the compoundof the formula (I-c),” “the compound of the formula (I-d),” and thelike, which are the subordinate concepts of “the compound of the formula(I).”

[16]

A sixteenth embodiment of the present invention is an intermediatecompound represented by the following formula (I′), or apharmaceutically acceptable salt thereof, or a solvate thereof:

wherein p represents an integer of 0 to 3; L represents a hydroxylgroup, a halogen atom, a C₁₋₆ alkoxyl group, a C₆₋₁₄ aryloxy group, or aC₇₋₂₀ aralkyloxy group; R¹ each independently represents a halogen atom,a hydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkyl group, aC₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆alkoxylcarbonyl group, a C₁₋₆ alkoxyl C₂₋₆ alkenyl group, a hydroxy C₁₋₆alkyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, aC₁₋₆ alkylthio group, a C₁₋₆ alkylsulfinyl group, a C₁₋₆ alkylsulfonylgroup, a 3- to 14-membered non-aromatic heterocyclic group, a 5- to7-membered monocyclic heteroaryl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group eachindependently represent a substituent selected from among a hydrogenatom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆alkyl group, a cyanated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₂₀aralkyl group, a heterocyclic group, a C₂₋₇ alkanoyl group, a hydroxyC₂₋₇ alkanoyl group, a halogenated C₂₋₇ alkanoyl group, a C₃₋₈cycloalkylcarbonyl group, a C₆₋₁₄ arylcarbonyl group, a C₇₋₂₀aralkylcarbonyl group, a heterocyclic carbonyl group, a mono-/di-C₁₋₆alkylcarbamoyl group, a mono-/di-halogenated C₁₋₆ alkylcarbamoyl group,a mono-/di-C₃₋₈ cycloalkylcarbamoyl group, a mono-/di-C₆₋₁₄arylcarbamoyl group, a mono-/di-C₇₋₂₀ aralkylcarbamoyl group, amono-/di-heterocyclic carbamoyl group, a C₁₋₆ alkylsulfonyl group, ahalogenated C₁₋₆ alkylsulfonyl group, a C₃₋₈ cycloalkylsulfonyl group, aC₆₋₁₄ arylsulfonyl group, a C₇₋₂₀ aralkylsulfonyl group, a heterocyclicsulfonyl group, a mono-/di-C₁₋₆ alkylsulfamoyl group, amono-/di-halogenated C₁₋₆ alkylsulfamoyl group, a mono-/di-C₃₋₈cycloalkylsulfamoyl group, a mono-/di-C₆₋₁₄ arylsulfamoyl group, amono-/di-C₇₋₂₀ aralkylsulfamoyl group, and a mono-/di-heterocyclicsulfamoyl group; R² represents a hydrogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆alkoxyl C₁₋₆ alkyl group;

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A is represented by the formula (II-31), prepresents an integer of 1 to 3; and R⁶ represents a hydrogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, or a hydroxy C₁₋₆alkyl group.[16-1]

Preferably, the intermediate compound of the above embodiment [16] is anintermediate compound represented by the above formula (I′) wherein pand L have the same definitions as those described in the embodiment[16]; R¹ each independently represents a halogen atom, a hydroxyl group,a nitro group, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkylgroup, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆alkoxyl group, a halogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxylcarbonylgroup, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, aC₁₋₆ alkoxyl C₂₋₆ alkenyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthiogroup, a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a —CONR⁷R⁸ groupwherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have thesame definitions as those described in the above embodiment [16]; R²represents a hydrogen atom, a C₁₋₆ alkyl group, or a halogenated C₁₋₆alkyl group;

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A is represented by the formula (II-31), prepresents an integer of 1 to 3; and R⁶ represents a hydrogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, or a hydroxy C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[16-1-2]

More preferably, the intermediate compound of the above embodiment [16]is an intermediate compound represented by the above formula (I′)wherein p and L have the same definitions as those described in theembodiment [16]; R¹ each independently represents a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a halogenatedC₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₂₋₆ alkenyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, an —NR^(7A)R^(8A) group, ora —CONR^(7A)R^(8A) group wherein R^(7A) and R^(8A) in the —NR^(7A)R^(8A)group and the —CONR^(7A)R^(8A) group each independently represent asubstituent selected from among a hydrogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, a C₂₋₇alkanoyl group, a hydroxy C₂₋₇ alkanoyl group, a halogenated C₂₋₇alkanoyl group, a C₁₋₆ alkylsulfonyl group, and a halogenated C₁₋₆alkylsulfonyl group; R² represents a hydrogen atom, a C₁₋₆ alkyl group,or a halogenated C₁₋₆ alkyl group;

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A is represented by the formula (II-31), prepresents an integer of 1 to 3; and R⁶ represents a hydrogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, or a hydroxy C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[16-1-2-2]

Even more preferably, the intermediate compound of the above embodiment[16] is an intermediate compound represented by the above formula (I′)wherein p, L, R², R⁶, and ring A represented by the partial structuralformula (II) have the same definitions as those described in theembodiment [16-1-2] provided that when the ring A is represented by theformula (II-31), p represents an integer of 1 to 3; and R¹ eachindependently represents a C₂₋₇ alkanoyl group, and has the samedefinitions as those described in the embodiment [16-1-2], or apharmaceutically acceptable salt thereof, or a solvate thereof.

[16-1-3]

Further preferably, the intermediate compound of the above embodiment[16] is an intermediate compound represented by the above formula (I′)wherein p and L have the same definitions as those described in theembodiment [16]; R¹ each independently represents a halogen atom, acyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, a halogenatedC₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆alkoxyl C₁₋₆ alkyl group, a C₁₋₆ alkoxyl C₂₋₆ alkenyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, an —NR^(A)R^(8A) group, ora —CONR^(7A)R^(8A) group wherein R^(7A) and R^(8A) in the —NR^(7A)R^(8A)group and the —CONR^(7A)R^(8A) group have the same definitions as thosedescribed in the above embodiment [16-1-2]; R² represents a hydrogenatom, a C₁₋₆ alkyl group, or a halogenated C₁₋₆ alkyl group;

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A is represented by the formula (II-31), prepresents an integer of 1 to 3; and R⁶ represents a hydrogen atom, aC₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, or a hydroxy C₁₋₆alkyl group, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[16-1-3-2]

Still further preferably, the intermediate compound of the aboveembodiment [16] is an intermediate compound represented by the aboveformula (I′) wherein p, L, R², R⁶, and ring A represented by the partialstructural formula (II) have the same definitions as those described inthe embodiment [16-1-3] provided that when the ring A is represented bythe formula (II-31), p represents an integer of 1 to 3; and R¹ eachindependently represents a C₂₋₇ alkanoyl group, and has the samedefinitions as those described in the embodiment [16-1-3], or apharmaceutically acceptable salt thereof, or a solvate thereof.

[16-1-4]

Particularly preferably, the intermediate compound of the aboveembodiment [16] is an intermediate compound represented by the aboveformula (I′) wherein p and L have the same definitions as thosedescribed in the embodiment [16]; R¹ each independently represents ahalogen atom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkylgroup, a halogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, or a C₁₋₆ alkoxyl C₂₋₆alkenyl group, and more specifically, R¹ represents fluorine, chlorine,a cyano group, a methyl group, an ethyl group, an isopropyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, avinyl group, a methoxy group, an ethoxyethyl group, a 2-ethoxyvinylgroup, or the like; R² represents a hydrogen atom or a C₁₋₆ alkyl group,and more specifically, R² represents a hydrogen atom, a methyl group, orthe like;

ring A represented by the following partial structural formula (II):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A is represented by the formula (II-31), prepresents an integer of 1 to 3; and R⁶ represents a hydrogen atom or aC₁₋₆ alkyl group, and more specifically, R⁶ represents a hydrogen atom,a methyl group, or the like, or a pharmaceutically acceptable saltthereof, or a solvate thereof.[16-1-4-2]

More particularly preferably, the intermediate compound of the aboveembodiment [16] is an intermediate compound represented by the aboveformula (I′) wherein p, L, R², R⁶, and ring A represented by the partialstructural formula (II) have the same definitions as those described inthe embodiment [16-1-4] provided that when the ring A is represented bythe formula (II-31), p represents an integer of 1 to 3; and R¹ eachindependently represents a C₂₋₇ alkanoyl group, and has the samedefinitions as those described in the embodiment [16-1-4], and morespecifically, R¹ represents fluorine, chlorine, a cyano group, a methylgroup, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, avinyl group, a methoxy group, an ethoxyethyl group, a 2-ethoxyvinylgroup, an acetyl group, or the like, or a pharmaceutically acceptablesalt thereof, or a solvate thereof.

[16-1-5]

Even more particularly preferably, the intermediate compound of theabove embodiment [16] is an intermediate compound represented by theabove formula (I′) wherein p, L, R¹, R², R⁶, and ring A have the samedefinitions as those described in the above embodiment [16-1-4-2], and aspecific ring A group, in which the definitions of the above describedp, R¹, and ring A are combined, represents a 1-methyl-1H-imidazol-4-ylgroup, a 4-(difluoromethyl)-5-ethylthiazol-2-yl group, a4-(difluoromethyl)-5-vinylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(difluoromethyl)thiazol-2-ylgroup, a 4-(trifluoromethyl)thiazol-2-yl group, a4-(trifluoromethyl)thiazol-2-yl group, a 4,5-dimethylthiazol-2-yl group,a 4-tert-butylthiazol-2-yl group, a 4-ethylthiazol-2-yl group, a4-cyanothiazol-2-yl group, a 4-methylthiazol-2-yl group, a4-methylthiazol-2-yl group, a 5-(2-ethoxyethyl)-4-methylthiazol-2-ylgroup, a 5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-methylthiazol-2-yl group, a 5-bromo-4-methylthiazol-2-ylgroup, a 5-methylthiazol-2-yl group, a thiazol-2-yl group, a2,5-dimethyl-thiazol-4-yl group, a 2-methylthiazol-4-yl group, a5-acetyl-2-methylthiazol-4-yl group, a 5-bromo-2-methylthiazol-4-ylgroup, a thiazol-4-yl group, a 3-isopropyl-1,2,4-thiadiazol-5-yl group,a 3-methyl-1,2,4-thiadiazol-5-yl group, a 5-ethyl-1,3,4-thiadiazol-2-ylgroup, a 5-methyl-1,3,4-thiadiazol-2-yl group, a5-(2-ethoxyvinyl)4-methylthiazol-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 4,6-dimethylpyrimidin-2-yl group, a 4-methylpyrimidin-2-ylgroup, a 2,5,6-trimethylpyrimidin-4-yl group, a2,5-dimethylpyrimidin-4-yl group, a 2,6-dimethylpyrimidin-4-yl group, a2,6-dimethoxypyrimidin-4-yl group, a 2-methylpyrimidin-4-yl group, a2-methoxypyrimidin-4-yl group, a 5,6-dimethylpyrimidin-4-yl group, a5-chloro-2-methylpyrimidin-4-yl group, a 5-chloropyrimidin-4-yl group, a5-fluoro-2-methylpyrimidin-4-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a5-fluoro-6-methylpyrimidin-4-yl group, a 5-methylpyrimidin-4-yl group, a5-methoxypyrimidin-4-yl group, a 6-methylpyrimidin-4-yl group, a6-methoxy-5-methylpyrimidin-4-yl group, a 4-methylpyridazin-3-yl group,a 5-methylpyridazin-3-yl group, a 6-methylpyridazin-3-yl group, apyridazin-3-yl group, a 3-cyanopyridin-2-yl group, a3-cyano-pyridin-2-yl group, a 3-methylpyridin-2-yl group, a3-methoxypyridin-2-yl group, a 4,6-dimethylpyridin-2-yl group, a4-fluoropyridin-2-yl group, a 4-methylpyridin-2-yl group, a4-methylpyridin-2-yl group, a 4-methoxypyridin-2-yl group, a4-methoxy-pyridin-2-yl group, a 5-cyanopyridin-2-yl group, a5-fluoropyridin-2-yl group, a 5-methylpyridin-2-yl group, a5-methylpyridin-2-yl group, a 6-(trifluoromethyl)pyridin-2-yl group, a6-cyano-pyridin-2-yl group, a 6-methylpyridin-2-yl group, a6-methoxypyridin-2-yl group, a 3,6-dimethylpyrazin-2-yl group, a3,6-dimethyl-pyrazin-2-yl group, a 3-methylpyrazin-2-yl group, a3-methoxypyrazin-2-yl group, a 5-methylpyrazin-2-yl group, a6-methylpyrazin-2-yl group, or a 6-methoxypyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[16-2]

An intermediate compound represented by the following formula (I′-a), ora pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein p, L, R¹, and R² have the same definitions as those described inthe above embodiment [16];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group.[16-2-2]

Preferably, the intermediate compound of the above embodiment [16-2] isan intermediate compound represented by the above formula (I′-a) whereinp, L, R¹, and R² have the same definitions as those described in theabove embodiment [16-1];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[16-2-3]

More preferably, the intermediate compound of the above embodiment[16-2] is an intermediate compound represented by the above formula(I′-a) wherein p, L, R¹, and R² have the same definitions as thosedescribed in the above embodiment [16-1-2-2];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[16-2-4]

Further preferably, the intermediate compound of the above embodiment[16-2] is an intermediate compound represented by the above formula(I′-a) wherein p, L, R¹, and R² have the same definitions as thosedescribed in the above embodiment [16-1-3-2];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.[16-2-5]

Particularly preferably, the intermediate compound of the aboveembodiment [16-2] is an intermediate compound represented by the aboveformula (I′-a) wherein p, L, R¹, and R² have the same definitions asthose described in the above embodiment [16-1-4-2];

ring A′ represented by the following partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom or a C₁₋₆ alkyl group, and morespecifically, R⁶ represents a hydrogen atom, a methyl group, or thelike, or a pharmaceutically acceptable salt thereof, or a solvatethereof.[16-2-6]

More particularly preferably, the intermediate compound of the aboveembodiment [16-2] is an intermediate compound represented by the aboveformula (I′-a) wherein p, L, R¹, R², R⁶, and ring A′ have the samedefinitions as those described in the above embodiment [16-2-5], and aspecific ring A′ group, in which the definitions of the above describedp, R¹, and ring A′ are combined, represents a 1-methyl-1H-imidazol-4-ylgroup, a 4-(difluoromethyl)-5-ethylthiazol-2-yl group, a4-(difluoromethyl)-5-vinylthiazol-2-yl group, a4-(difluoromethyl)-5-methylthiazol-2-yl group, a4-(difluoromethyl)thiazol-2-yl group, a 4-(trifluoromethyl)thiazol-2-ylgroup, a 4,5-dimethylthiazol-2-yl group, a 4-tert-butylthiazol-2-ylgroup, a 4-ethylthiazol-2-yl group, a 4-cyanothiazol-2-yl group, a4-methylthiazol-2-yl group, a 4-methylthiazol-2-yl group, a5-(2-ethoxyethyl)-4-methylthiazol-2-yl group, a5-chloro-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl group, a5-cyclopropyl-4-methylthiazol-2-yl group, a 5-bromo-4-methylthiazol-2-ylgroup, a 5-methylthiazol-2-yl group, a thiazol-2-yl group, a2,5-dimethyl-thiazol-4-yl group, a 2-methylthiazol-4-yl group, a5-acetyl-2-methylthiazol-4-yl group, a 5-bromo-2-methylthiazol-4-ylgroup, a thiazol-4-yl group, a 3-isopropyl-1,2,4-thiadiazol-5-yl group,a 3-methyl-1,2,4-thiadiazol-5-yl group, a 5-ethyl-1,3,4-thiadiazol-2-ylgroup, a 5-methyl-1,3,4-thiadiazol-2-yl group, or a5-(2-ethoxyvinyl)4-methylthiazol-2-yl group, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

[16-3]

An intermediate compound represented by the following formula (I′-b), ora pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein p, L, R¹, and R² have the same definitions as those described inthe above embodiment [16];

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A″ is represented by the formula (II-31), prepresents an integer of 1 to 3.[16-3-2]

Preferably, the intermediate compound of the above embodiment [16-3] isan intermediate compound represented by the above formula (I′-b) whereinp, L, R¹, and R² have the same definitions as those described in theabove embodiment [16-1]; and ring A″ represented by the partialstructural formula (II″) has the same definitions as those described inthe above embodiment [16-3] provided that when the ring A″ isrepresented by the formula (II-31), p represents an integer of 1 to 3,or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[16-3-3]

More preferably, the intermediate compound of the above embodiment[16-3] is an intermediate compound represented by the above formula(I′-b) wherein p, L, R¹, and R² have the same definitions as thosedescribed in the above embodiment [16-1-2-2]; and ring A″ represented bythe partial structural formula (II″) has the same definitions as thosedescribed in the above embodiment [16-3] provided that when the ring A″is represented by the formula (II-31), p represents an integer of 1 to3, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[16-3-4]

Further preferably, the intermediate compound of the above embodiment[16-3] is an intermediate compound represented by the above formula(I′-b) wherein p, L, R¹, and R² have the same definitions as thosedescribed in the above embodiment [16-1-3-2]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A″ is represented by the formula (II-31), prepresents an integer of 1 to 3, or a pharmaceutically acceptable saltthereof, or a solvate thereof.[16-3-5]

Particularly preferably, the intermediate compound of the aboveembodiment [16-3] is an intermediate compound represented by the aboveformula (I′-b) wherein p, L, R¹, and R² have the same definitions asthose described in the above embodiment [16-1-4-2]; and

ring A″ represented by the following partial structural formula (II″):

is selected from the group of the heteroaryls consisting of thefollowing:

provided that when the ring A″ is represented by the formula (II-31), prepresents an integer of 1 to 3, or a pharmaceutically acceptable saltthereof, or a solvate thereof.[16-3-6]

More particularly preferably, the intermediate compound of the aboveembodiment [16-3] is an intermediate compound represented by the aboveformula (I′-b) wherein p, L, R¹, R², and ring A″ have the samedefinitions as those described in the above embodiment [16-3-5], and aspecific ring A″ group, in which the definitions of the above describedp, R¹, and ring A″ are combined, represents a 4,6-dimethylpyrimidin-2-ylgroup, a 4-methylpyrimidin-2-yl group, a 2,5,6-trimethylpyrimidin-4-ylgroup, a 2,5-dimethylpyrimidin-4-yl group, a 2,6-dimethylpyrimidin-4-ylgroup, a 2,6-dimethoxypyrimidin-4-yl group, a 2-methylpyrimidin-4-ylgroup, a 2-methoxypyrimidin-4-yl group, a 5,6-dimethylpyrimidin-4-ylgroup, a 5-chloro-2-methylpyrimidin-4-yl group, a 5-chloropyrimidin-4-ylgroup, a 5-fluoro-2-methylpyrimidin-4-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a5-fluoro-6-methylpyrimidin-4-yl group, a 5-methylpyrimidin-4-yl group, a5-methoxypyrimidin-4-yl group, a 6-methylpyrimidin-4-yl group, a6-methoxy-5-methylpyrimidin-4-yl group, a 4-methylpyridazin-3-yl group,a 5-methylpyridazin-3-yl group, a 6-methylpyridazin-3-yl group, apyridazin-3-yl group, a 3-cyano-pyridin-2-yl group, a3-methylpyridin-2-yl group, a 3-methoxypyridin-2-yl group, a4,6-dimethylpyridin-2-yl group, a 4-fluoropyridin-2-yl group, a4-methylpyridin-2-yl group, a 4-methoxypyridin-2-yl group, a5-cyanopyridin-2-yl group, a 5-fluoropyridin-2-yl group, a5-methylpyridin-2-yl group, a 6-(trifluoromethyl)pyridin-2-yl group, a6-cyano-pyridin-2-yl group, a 6-methylpyridin-2-yl group, a6-methoxypyridin-2-yl group, a 3,6-dimethyl-pyrazin-2-yl group, a3-methylpyrazin-2-yl group, a 3-methoxypyrazin-2-yl group, a5-methylpyrazin-2-yl group, a 6-methylpyrazin-2-yl group, a6-methylpyrazin-2-yl group, or a 6-methoxypyrazin-2-yl group, or apharmaceutically acceptable salt thereof, or a solvate thereof.

[17]

A seventeenth embodiment of the present invention is illustrated, by wayof example, with the below-listed intermediate compounds that arepreferable as the compounds of the above embodiment [16] represented bythe above formula (I′), the compounds of the above embodiment [16-2]represented by the above formula (I′-a), and the compounds of the aboveembodiment [16-3] represented by the above formula (I′-b), orpharmaceutically acceptable salts thereof, or their solvates. The shownintermediate compounds are obtained from individual steps with Examplenumbers corresponding to compound names. For example, in the case ofExample number 1.1-2, it means that an intermediate compoundcorresponding to (Example 1.1) <Step 2> is obtained. It is to be notedthat the following compound names are based on English names obtained inaccordance with the chemical nomenclature program of Cambridge Soft ChemBioDraw Ultra 12.0.2.1076.

TABLE 2-1 Compound name Example No. methyl1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5- 1.1-2 carboxylate1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-car- 1.1-3 boxylic acidmethyl 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole- 1.2-15-carboxylate 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-car- 1.2-2boxylic acid methyl 4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-1.3-1 pyrazole-5-carboxylate methyl4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1- 1.4-1methyl-1H-pyrazole-5-carboxylate methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1- 1.4-2methyl-1H-pyrazole-5-carboxylate methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H- 1.5-1pyrazole-5-carboxylate methyl1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H- 1.6-1pyrazole-5-carboxylate

TABLE 2-2 Example Compound name No. methyl4-(5-chloro-4-(difluoromethyl)thiazol-2-y1)-1-methyl-1H-  1.7-1pyrazole-5-carboxylate4-(5-chloro-4-(difluoromethyl)thiazol-2-y1)-1-methyl-  1.7-21H-pyrazole-5-carboxylic acid methyl4-(4,5-dimethylthiazol-2-y1)-1-methyl-1H-pyrazole-5-  2.2-1 carboxylate4-(4,5-dimethylthiazol-2-y1)-1-methyl-1H-  2.2-2 pyrazole-5-carboxylicacid 1-methyl-4-(4-(trifluoromethyl)thiazol-2-y1)-1H-pyrazole-  2.8-15-carboxylicacid methyl 1-methyl-4-(6-methylpyridin-2-y1)-1H-pyrazole- 2.9-1 5-carboxylate methyl 1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-y1)-2.10-1 1H-pyrazole-5-carboxylate1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-y1)-1H-pyrazole- 2.10-25-carboxylic acid methyl4-(6-methoxypyridin-2-y1)-1-methyl-1H-pyrazole-5- 2.11-1 carboxylate4-(6-methoxypyridin-2-y1)-1-methyl-1H-pyrazole- 2.11-2 5-carboxylic acidmethyl 1-methyl-4-(2-methylthiazol-4-y1)- 2.12-11H-pyrazole-5-carboxylate

TABLE 2-3 Example Compound name No. methyl1-methyl-4-(6-methylpyrazin-2-y1)-1H-pyrazole- 2.13-1 5-carboxylate1-methyl-4-(6-methylpyrazin-2-y1)-1H-pyrazole-5-carboxylic acid 2.13-2methyl 4-(3-isopropy1-1,2,4-thiadiazol-5-y1)-1-methyl-1H- 2.14-1pyrazole-5-carboxylate methyl1-methy1-4-(5-methylthiazol-2-y1)-1H-pyrazole- 2.15-1 5-carboxylatemethyl 1-methyl-4-(4-methylpyrimidin-2-y1)-1H-pyrazole-5- 2.16-1carboxylate 1-methyl-4-(4-methylpyrimidin-2-y1)-1H-pyrazole- 2.16-25-carboxylic acid methyl1-methyl-4-(1-methyl-1H-imidazol-4-y1)-1H-pyrazole-5- 2.17-1 carboxylate1-methyl-4-(4-(trifluoromethyl)thiazol-2-y1)-1H-pyrazole- 2.19-75-carboxylic acid methyl1-methyl-4-(thiazol-4-y1)-1H-pyrazole-5-carboxylate 2.25-1 methyl1-methyl-4-(thiazol-2-y1)-1H-pyrazole-5-carboxylate 2.26-1 methyl4-(4-(tert-butyl)thiazol-2-y1)-1-methyl-1H-pyrazole-5- 2.27-1carboxylate methyl 1-methyl-4-(3-methylpyridin-2-y1)-1H-  3.1-2pyrazole-5-carboxylate1-methyl-4-(3-methylpyridin-2-y1)-1H-pyrazole-5-carboxylic acid  3.1-3

TABLE 2-4 Example Compound name No.1-methyl-4-(5-methylpyrazin-2-y1)-1H-pyrazole-5-carboxylic acid 3.2-11-methyl-4-(6-methylpyridin-2-y1)-1H-pyrazole-5-carboxylic acid 3.3-14-(4-fluoropyridin-2-y1)-1-methyl-1H-pyrazole-5-carboxylic acid 3.4-11-methyl-4-(4-methylpyridin-2-y1)-1H-pyrazole-5-carboxylic acid 3.5-11-methyl-4-(4-(trifluoromethyl)thiazol-2-y1)-1H-pyrazole- 3.6-15-carboxylic acid 4-(3-methoxypyridin-2-y1)-1-methyl-1H-pyrazole-5-3.7-1 carboxylic acid4-(5-fluoropyridin-2-y1)-1-methyl-1H-pyrazole-5-carboxylic acid 3.8-1methyl 1-methyl-4-(6-methylpyrazin-2-y1)-1H-pyrazole- 3.9-15-carboxylate 1-methyl-4-(6-methylpyrazin-2-y1)-1H-pyrazole-5-carboxylicacid 3.9-2 1-methyl-4-(6-(trifluoromethyl)pyridin-2-y1)-1H-pyrazole-5-3.10-1  carboxylic acid4-(4,6-dimethylpyridin-2-y1)-1-methyl-1H-pyrazole-5- 3.11-1  carboxylicacid 4-(4-difluoromethyl)thiazol-2-y1)-1-methyl-1H-pyrazole- 3.12-1 5-carboxylic acid methyl 4-(3-cyanopyridin-2-y1)-1-methyl-1H-pyrazole-3.13-1  5-carboxylate4-(3-cyanopyridin-2-y1)-1-methyl-1H-pyrazole-5-carboxylic acid 3.13-2 

TABLE 2-5 Example Compound name No. methyl4-(3,6-dimethylpyrazin-2-y1)-1-methyl-1H-pyrazole-5- 3.14-1 carboxylate4-(3,6-dimethylpyrazin-2-y1)-1-methyl-1H-pyrazole-5- 3.14-2 carboxylicacid methyl 4-(4-ethylthiazol-2-y1)-1-methy1-1H-pyrazole- 3.18-15-carboxylate 4-(4-ethylthiazol-2-y1)-1-methyl-1H-pyrazole-5-carboxylicacid 3.18-2 methyl4-(2,5-dimethylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.22-1carboxylate 4-(2,5-dimethylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5-3.22-2 carboxylic acid4-(5-cyanopyridin-2-y1)-1-methyl-1H-pyrazole-5-carboxylic acid 3.23-1methyl 1-methyl-4-(4-methylpyridazin-3-y1)-1H-pyrazole-5- 3.24-1carboxylate 1-methyl-4-(4-methylpyridazin-3-y1)-1H-pyrazole-5- 3.24-2carboxylic acid methyl1-methyl-4-(2-methylpyrimidin-4-y1)-1H-pyrazole-5- 3.25-1 carboxylate1-methyl-4-(2-methylpyrimidin-4-y1)-1H-pyrazole- 3.25-2 5-carboxylicacid methyl 4-(2-methoxypyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.26-1carboxylate 4-(2-methoxypyrimidin-4-y1)-1-methyl-1H-pyrazole- 3.26-25-carboxylic acid methyl 4-(5-fluoro-2-methoxypyrimidin-4-y1)-1-methyl-3.27-1 1H-pyrazole-5-carboxylate

TABLE 2-6 Example Compound name No.4-(5-fluoro-2-methoxypyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.27-2carboxylic acid methyl 4-(3-methoxypyrazin-2-y1)-1-methyl-1H-pyrazole-5-3.28-1 carboxylate 4-(3-methoxypyrazin-2-y1)-1-methyl-1H-pyrazole-3.28-2 5-carboxylic acid methyl4-(5-chloropyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.29-1 carboxylate4-(5-chloropyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.29-2 carboxylicacid methyl 4-(2,6-dimethylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5-3.30-1 carboxylate4-(2,6-dimethylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.30-2 carboxylicacid methyl 4-(6-methoxy-5-methylpyrimidin-4-y1)-1-methyl- 3.31-11H-pyrazole-5-carboxylate4-(6-methoxy-5-methylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.31-2carboxylic acid methyl 1-methy1-4-(3-methylpyrazin-2-y1)-1H-pyrazole-3.32-1 5-carboxylate1-methyl-4-(3-methylpyrazin-2-y1)-1H-pyrazole-5-carboxylic acid 3.32-2methyl 1-methy1-4-(5-methylpyrimidin-4-y1)-1H-pyrazole-5- 3.33-1carboxylate 1-methyl-4-(5-methylpyrimidin-4-y1)-1H-pyrazole-5- 3.33-2carboxylic acid methyl4-(5-methoxypyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.34-1 carboxylate

TABLE 2-7 Example Compound name No.4-(5-methoxypyrimidin-4-y1)-1-methyl-1H-pyrazole- 3.34-2 5-carboxylicacid methyl 4-(5,6-dimethylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5-3.35-1 carboxylate 4-(5,6-dimethylpyrimidin-4-y1)-1-methyl-1H-pyrazole-3.35-2 5-carboxylic acid methyl4-(5-fluoro-2-methylpyrimidin-4-y1)-1-methyl- 3.36-11H-pyrazole-5-carboxylate4-(5-fluoro-2-methylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.36-2carboxylic acid methyl 1-methyl-4-(2,5,6-trimethylpyrimidin-4-y1)-1H-3.37-1 pyrazole-5-carboxylate1-methyl-4-(2,5,6-trimethylpyrimidin-4-y1)-1H-pyrazole-5- 3.37-2carboxylic acid methyl 4-(5-fluoro-6-methylpyrimidin-4-y1)-1-methyl-1H-3.38-1 pyrazole-5-carboxylate4-(5-fluoro-6-methylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.38-2carboxylic acid methyl1-methyl-4-(6-methylpyrimidin-4-y1)-1H-pyrazole-5- 3.39-1 carboxylate1-methyl-4-(6-methylpyrimidin-4-y1)-1H-pyrazole-5- 3.39-2 carboxylicacid methyl 4-(2,6-dimethoxypyrimidin-4-y1)-1-methyl-1H- 3.40-1pyrazole-5-carboxylate4-(2,6-dimethoxypyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.40-2carboxylic acid methyl 4-(5-chloro-2-methylpyrimidin-4-y1)-1-methyl-3.41-1 1H-pyrazole-5-carboxylate

TABLE 2-8 Example Compound name No.4-(5-chloro-2-methylpyrimidin-4-y1)-1-methyl-1H-pyrazole-5- 3.41-2carboxylic acid methyl 4-(6-methoxypyrazin-2-y1)-1-methyl-1H-pyrazole-5-3.42-1 carboxylate 4-(6-methoxypyrazin-2-y1)-1-methyl-1H-pyrazole-5-3.42-2 carboxylic acid methyl1-methyl-4-(4-methylpyrimidin-2-y1)-1H-pyrazole-5- 3.43-1 carboxylate1-methyl-4-(4-methylpyrimidin-2-y1)-1H-pyrazole-5- 3.43-2 carboxylicacid methyl 4-(4,6-dimethylpyrimidin-2-y1)-1-methyl-1H-pyrazole-5-3.44-1 carboxylate 4-(4,6-dimethylpyrimidin-2-y1)-1-methyl-1H-pyrazole-3.44-2 5-carboxylic acid methyl1-methyl-4-(6-methylpyridazin-3-y1)-1H-pyrazole-5- 3.45-1 carboxylate1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole- 3.45-2 5 -carboxylicacid methyl 1-methyl-4-(5-methylpyridazin-3-y1)-1H-pyrazole-5- 3.46-1carboxylate 1-methyl-4-(5-methylpyridazin-3 -yl)-1H-pyrazole- 3.46-25-carboxylic acid methyl1-methyl-4-(pyridazin-3-y1)-1H-pyrazole-5-carboxylate 3.47-11-methyl-4-(pyridazin-3-y1)-1H-pyrazole-5-carboxylic acid 3.47-2 methyl1-methyl-4-(4-methylpyridin-2-y1)-1H-pyrazole-5-  4.4-1 carboxylate

TABLE 2-9 Example Compound name No.1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic 4.4-2 acidmethyl 4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5- 4.5-1carboxylate 4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic4.5-2 acid methyl 4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-4.8-1 5-carboxylate4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic 4.8-2acid 4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H- 4.9-1pyrazole-5-carboxylic acid1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5- 4.10-1carboxylic acid methyl4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5- 5.4-1 carboxylatemethyl 4-(4-(difluoromethyl)-5-vinylthiazol-2-yl)-1-methyl-1H- 5.5-1pyrazole-5-carboxylate methyl4-(4-(difluoromethyl)-5-ethylthiazol-2-yl)-1-methyl-1H- 5.6-1pyrazole-5-carboxylate methyl4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-1- 5.8-1methyl-1H-pyrazole-5-carboxylate4-(4-cyanothiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid 5.10-1

TABLE 2-10 Example Compound name No. methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole- 5.11-15-carboxylate (E)-methyl4-(5-(2-ethoxyyinyl)-4-methylthiazol-2-yl)-1-methyl- 5.11-21H-pyrazole-5-carboxylate methyl4-(5-(2-ethoxyethyl)-4-methylthiazol-2-yl)-1-methyl-1H- 5.11-3pyrazole-5-carboxylate methyl4-(5-ethyl-1,3,4-thiadiazol-2-yl)-1-methyl-1H-pyrazole-5- 5.12-1carboxylate methyl4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-1H-pyrazole- 5.13-15-carboxylate methyl1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrazole- 5.15-15-carboxylate methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole- 5.38-15-carboxylate4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5- 5.38-2carboxylic acid4-(2,5-dimethylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic 5.39-1acid 4-(6-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid5.40-1 4-(4-cyanothiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid5.41-1 methyl 4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-1H- 5.43-1pyrazole-5-carboxylate

TABLE 2-11 Example Compound name No. methyl4-(5-acetyl-2-methylthiazol-4-yl)-1-methyl-1H- 5.44-1pyrazole-5-carboxylate4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5- 5.45-1 carboxylicacid 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carbonyl 5.47-1chloride

In all of the above described embodiments, when the term “compound” isused, it also refers to a “pharmaceutically acceptable salt thereof”

There may be a case in which the compound in the present invention formsan acid addition salt or a salt with a base, depending on the type of asubstituent. Such salts are not particularly limited, as long as theyare pharmaceutically acceptable salts. Examples of the salts includemetal salts, ammonium salts, salts with organic bases, salts withinorganic acids, salts with organic acids, and salts with basic oracidic amino acids. Preferred examples of the metal salts include:alkaline metal salts, such as lithium salts, sodium salts, potassiumsalts, and cesium salts; alkaline-earth metal salts such as calciumsalts, magnesium salts, and barium salts; and aluminum salts (whereinthe salts include disodium salts and dipotassium salts, as well as monosalts). Preferred examples of the salts with organic bases include saltswith methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine,trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine,dibenzylamine, ethanolamine, diethanolamine, triethanolamine,piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine,ethylenediamine, N-methylglucamine, glucosamine,phenylglycinealkylester, guanidine, 2,6-lutidine, ethanolamine,diethanolamine, triethanolamine, and N,N′-dibenzylethylenediamine.Preferred examples of the salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,sulfuric acid, and phosphoric acid. Preferred examples of the salts withorganic acids include: salts with aliphatic monocarboxylic acids such asformic acid, acetic acid, trifluoroacetic acid, propionic acid, butyricacid, valeric acid, enanthic acid, capric acid, myristic acid, palmiticacid, stearic acid, lactic acid, sorbic acid, and mandelic acid; saltswith aliphatic dicarboxylic acids such as oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid;salts with aliphatic tricarboxylic acids such as citric acid; salts witharomatic monocarboxylic acids such as benzoic acid and salicylic acid;salts with aromatic dicarboxylic acids such as phthalic acid; salts withorganic carboxylic acids such as cinnamic acid, glycolic acid, pyruvicacid, oxyl acid, salicylic acid, and N-acetyl cysteine; salts withorganic sulfonic acids such as methanesulfonic acid, benzenesulfonicacid, and p-toluenesulfonic acid; and acid addition salts with acidicamino acids such as aspartic acid and glutamic acid. Preferred examplesof the salts with basic amino acids include salts with arginine, lysine,and ornithine. Preferred examples of the salts with acidic amino acidsinclude salts with aspartic acid and glutamic acid. Among these salts,pharmaceutically acceptable salts are preferable. For example, when thecompound has an acidic functional group therein, examples of the saltsinclude inorganic salts such as alkaline metal salts (e.g. sodium saltsand potassium salts) and alkaline-earth metal salts (e.g. calcium salts,magnesium salts, and barium salts), and ammonium salts. When thecompound has a basic functional group therein, examples of the saltsinclude: salts with inorganic acids such as hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; andsalts with organic acids such as acetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, methanesulfonic acid and p-toluenesulfonic acid.

The above described salts can be obtained according to an ordinarymethod, for example, by mixing the compound in the present inventionwith a solution containing an appropriate amount of acid or base to formsalts of interest, and then subjecting the salts to fractionation byfiltration, or distilling the mixed solvent away from the reactionsolution. Moreover, the compound in the present invention or a saltthereof can form a solvate with a solvent such as water, ethanol, orglycerol.

Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl& Wermuth (Wiley-VCH, 2002) has been published as a review bookregarding salts. This book includes detailed descriptions regardingsalts.

The compound in the present invention can be present in an unsolvatedstate or a solvated state. In the present specification, the term“solvate” means a molecular complex comprising the compound in thepresent invention and one or more pharmaceutically acceptable solventmolecules (e.g. water and ethanol). When the aforementioned solventmolecule is water, it is particularly referred to as a “hydrate.”

Hereinafter, the descriptions regarding the compound in the presentinvention include the descriptions regarding the salt thereof, thesolvate thereof, and a solvate of the salt.

The “prodrug” of the compound in the present invention is also includedin the compound in the present invention. For instance, when a certainderivative of the compound in the present invention, which may hardly ornever exhibit pharmacological activities of interest, is converted tothe compound in the present invention having the pharmacologicalactivities of interest, for example, as a result of hydrolysis or thelike, following administration into or on a body, the compound beforeadministration is referred to as a “prodrug.”

A “prodrug” of the compound in the present invention can be produced,for example, by subjecting a suitable functional group present in thecompound in the present invention to a known method, for example, themethod described in Design of Prodrugs, H. Bundgaard (Elsevier, 1985).

Specific examples of the “prodrug” of the compound in the presentinvention may include the following (1) to (3), but examples are notlimited thereto.

(1) Case in which the compound in the present invention is substitutedwith a carboxy group (—COOH): the ester thereof, namely, a compound inwhich the hydrogen atom of the carboxy group (—COOH) is replaced with a“C₁₋₆ alkyl group.”(2) Case in which the compound in the present invention is substitutedwith a hydroxyl group (—OH): the alkanoyloxy or the ether thereof,namely, a compound in which the hydrogen atom of the hydroxyl group(—OH) is replaced with a “C₂₋₇ alkanoyl group” or a “C₂₋₇alkanoyloxymethyl group.”(3) Case in which the compound in the present invention is substitutedwith an amino group (—NH₂ or —NHR′ (wherein R′≠H)): the amide thereof,namely, a compound in which either hydrogen atom or both hydrogen atomsof the amino group (—NH₂ or —NHR′ (wherein R′≠H)) are replaced with“C₂₋₇ alkanoyl groups.”

When the compound in the present invention has isomers such as ageometrical isomer, a configurational isomer, a tautomeric isomer, anoptical isomer, a diastereomer, a regioisomer, or a rotational isomer,both any one isomer and a mixture thereof are included in the compoundin the present invention. Moreover, when the compound in the presentinvention has an optical isomer, an optical isomer obtained from aracemate is also included in the compound in the present invention.

In the case of the compound in the present invention has one or moreasymmetric carbon atoms, two or more isomers can be present. Inaddition, when the compound in the present invention comprises a “C₂₋₆alkenyl group,” geometrical isomer (cis/trans or Z/E) can be present.Moreover, structural isomers can be mutually converted because of lowenergy barrier, tautomeric isomerism may be generated. An example ofsuch tautomeric isomerism is protonic tautomeric isomerism in a compoundhaving an imino, keto, or oxime group.

When the compound in the present invention has a geometrical isomer, aconfigurational isomer, a diastereomer, a conformer or the like, theseisomers can be each isolated by a known means.

Furthermore, when the compound in the present invention is an opticallyactive substance, a racemate can be separated into a (+) form or a (−)form [D form or L form] according to an ordinary optical resolutionmeans.

When the compound in the present invention contains an optical isomer, adiastereomer, a regioisomer, a rotational isomer, or a tautomericisomer, each isomer can be obtained as a single compound according to aknown synthetic method or separation method. Examples of the opticalresolution method include known methods such as (1) a fractionalrecrystallization method, (2) a diastereomer method, and (3) a chiralcolumn method.

(1) Fractional recrystallization method: This is a method whichcomprises binding an optical resolution agent to a racemate via an ionicbond to obtain a crystalline diastereomer, then separating thisdiastereomer by a fractional recrystallization method, and thensubjecting the resultant to a neutralization step, as desired, so as toobtain a free optically pure compound. Examples of the opticalresolution agent include (+)-mandelic acid, (−)-mandelic acid,(+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine,(−)-1-phenethylamine, cinchonine, (−)-cinchonidine, and brucine.

(2) Diastereomer method: This is a method which comprises binding via acovalent bond (reacting) an optical resolution agent to a racematemixture to form a diastereomer mixture, then subjecting the diastereomermixture to a common separation means (e.g., fractionalrecrystallization, silica gel column chromatography, and HPLC (highperformance liquid chromatography)) to separate it into an opticallypure diastereomer, and then removing the optical resolution agent by achemical treatment such as a hydrolysis reaction, so as to obtain anoptically pure optical isomer. For example, when the compound in thepresent invention has an intramolecular hydroxyl group or a primary orsecondary amino group, the compound and an optically active organic acid(e.g., MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid] and(−)-menthoxyacetic acid) or the like are subjected to a condensationreaction, so as to obtain a diastereomer of each ester body or amidebody. On the other hand, when the compound in the present invention hasa carboxy group, the compound and an optically active amine or analcohol reagent are subjected to a condensation reaction, so as toobtain a diastereomer of each amide body or ester body. Each of theabove separated diastereomers is converted to an optical isomer of theoriginal compound by subjecting it to an acidic hydrolysis or basichydrolysis reaction.

(3) Chiral column method: This is a method which comprises subjecting aracemate or a salt thereof to chromatography using a chiral column(optical isomer separatory column) for direct optical resolution. Forexample, in the case of high performance liquid chromatography (HPLC), amixture of optical isomers is added to a chiral column of CHIRAL Seriesmanufactured by Daicel Corporation, etc., and it is then developed by asingle use of water, various buffers (e.g., a phosphate buffer), andorganic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, and diethylamine), or using a mixed solutionthereof, thereby separating the optical isomer. In addition, forexample, in the case of gas chromatography, the optical isomer can beseparated using a chiral column of CP-Chirasil-DeX CB (manufactured byGL Sciences), etc.

The compound in the present invention may be a crystal. Although thecrystalline form is either a single crystal or a crystalline mixture,they are included in the compound in the present invention.

The compound in the present invention may be a pharmaceuticallyacceptable cocrystal or a cocrystal salt. Herein, the term “cocrystal”or “cocrystal salt” means a crystalline substance composed of two ormore unique solids at room temperature, which has each differentphysical properties (e.g. structure, melting point, melting heat,absorbency, solubility, and stability). Such a cocrystal or cocrystalsalt can be produced according to a known cocrystallization method.

The compound in the present invention includes compounds labeled orsubstituted with isotopes (e.g. hydrogen isotopes such as ²H and ³H,carbon isotopes such as ¹¹C, ¹³C, and ¹⁴C, chlorine isotopes such as³⁶Cl, fluorine isotopes such as ¹⁸F, iodine isotopes such as ¹²³I and¹²⁵I, nitrogen isotopes such as ¹³N and ¹⁵N, oxygen isotopes such as¹⁵O, ¹⁷O, and ¹⁸O, phosphorus isotopes such as ³²P, and sulfur isotopessuch as ³⁵S).

The compound in the present invention, which is labeled or substitutedwith certain types of isotopes (e.g. positron emission isotopes such as¹¹C, ¹⁸F, ¹⁵O, and ¹³N), can be used, for example, as a tracer (PETtracer) in Positron Emission Tomography (PET), and thus, it is useful inthe field such as medical diagnosis.

The compound in the present invention, which is labeled or substitutedwith certain types of isotopes, is useful for studies regardinghistological distribution of drugs and/or substrates. For instance, ³Hand ¹⁴C facilitate such labeling and substitution, and the detectionmeans is easy. Thus, they are useful for the aforementioned studypurpose.

The compound in the present invention, which is labeled with isotopes,can be obtained by a common technique known to a person skilled in theart, or by a method similar to the synthetic methods described later inExamples. In addition, instead of a non-labeled compound, the obtainedisotope-labeled compound can be used in pharmacological experiments.

[Method for Producing the Compound in the Present Invention]

Hereinafter, a method for producing the compound represented by theformula (I) of the present invention will be described. The compoundrepresented by the formula (I) that is the compound in the presentinvention, a salt thereof, and a solvate thereof can be easily producedby a combination of known general chemical production methods, using, asstarting materials or synthetic intermediates, commercially availablecompounds, or compounds that can be easily obtained from suchcommercially available compounds according to production methods knownfrom literature. They can be produced according to representativeproduction methods, as described below. In addition, the below-mentionedproduction methods are not intended to limit the present invention.

The definitions of p, q, Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, ring A, andfused ring B, which are used in individual formulas of thebelow-mentioned production methods, are the same as those described inthe formula (I) in the above described embodiments, unless otherwisespecified. The definition of M in the production method is metal such aslithium, sodium, or potassium, unless otherwise specified. Thedefinition of X in the production method is a halogen atom, unlessotherwise specified. The definition of Y in the production method is ahydrogen atom, a hydroxyl group, OR^(A), or chlorine, unless otherwisespecified. The definition of R^(A) in the production method is a C₁₋₆alkyl group, a C₆₋₁₃ aryl group, or a C₇₋₂₀ aralkyl group, unlessotherwise specified.

Individual raw material compounds used in the production of the compoundof the formula (I) in the below-mentioned production methods may formsalts. As such salts, the same salts as those in the above formula (I)may be included. In addition, each raw material compound used in theproduction of the compound of the formula (I) can be directly used as areaction solution, or as a crude product, in the subsequent reaction. Itcan also be isolated from a reaction mixture according to an ordinarymethod, and it can be easily purified by known separation means such asextraction, concentration, neutralization, filtration, distillation,recrystallization, or chromatography.

Examples of the solvent used in the above described recrystallizationinclude: water; alcohols such as methanol, ethanol, 2-propanol, andbutanol; ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane;hydrocarbons such as n-hexane, cyclohexane, and heptane; aromatichydrocarbons such as benzene, toluene, and xylene; amides such asN,N-dimethylformamide, N,N-dimethylacetamide, and1,3-dimethyl-2-imidazolidinone; halogenated hydrocarbons such aschloroform, methylene chloride, and 1,2-dichloroethane; nitriles such asacetonitrile; ketones such as acetone and diphenylketone; esters such asmethyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide;and organic acids such as acetic acid, trifluoroacetic acid,methanesulfonic acid, and p-toluenesulfonic acid. These solvents may beused singly, or may also be used by mixing two or more solvents at asuitable ratio, for example, at a ratio of 1:1 to 1:10. Moreover, when acompound represented by a formula is commercially available product, thecommercially available product may be directly used. Furthermore, acompound produced by a known method or a method equivalent thereto mayalso be used.

When a substituent in the formula (I) contains a variable functionalgroup (e.g. a carboxy group, an amino group, a hydroxyl group, acarbonyl group, a mercapto group, a C₁₋₆ alkoxylcarbonyl group, a C₆₋₁₄aryloxycarbonyl group, a C₇₋₂₀ aralkyloxycarbonyl group, a sulfo group(—SO₂OH), and a halogen atom), these functional groups are converted bya known method or a method equivalent thereto, so as to produce variouscompounds.

When the functional group is a “carboxy group,” it can be convertedaccording to reactions such as esterification, reduction, amidation, orconversion reaction to an optionally protected amino group.

When the functional group is an “amino group,” it can be convertedaccording to reactions such as amidation, sulfonylation, nitrosation,alkylation, arylation, or imidation.

When the functional group is a “hydroxyl group,” it can be convertedaccording to reactions such as esterification carbamoylation,sulfonylation, alkylation, arylation, oxidation, or halogenation.

When the functional group is a “carbonyl group,” it can be convertedaccording to reactions such as reduction, oxidation, imination(including oximation and conversion to hydrazone), (thio)ketalization,conversion to alkylidene, or thiocarbonylation.

When the functional group is a “mercapto group (—SH),” it can beconverted according to reactions such as alkylation or oxidation.

When the functional group is a “C₁₋₆ alkoxylcarbonyl group,” a “C₆₋₁₄aryloxycarbonyl group,” or a “C₇₋₂₀ aralkyloxycarbonyl group,” it can beconverted according to reactions such as reduction or hydrolysis.

When the functional group is a “sulfo group (—SO₂OH),” it can beconverted according to reactions such as sulfonamidation or reduction.

When the functional group is a “halogen atom,” it can be convertedaccording to, for example, various types of nucleophilic substitutionreactions or various types of coupling reactions.

In each of the above described reactions, when a compound is obtained inthe free state, it may be converted to salts according to an ordinarymethod. When the compound is obtained in the form of salts, the saltsmay also be converted to a free body or other salts according to anordinary method.

Conversion of these functional groups can be carried out according tothe method described, for example, in Richard C. Larock et al.,Comprehensive Organic Transformations, 2^(nd) edition, published inOctober, 1999, Wiley-VCH.

Moreover, in each reaction in the method for producing the compoundrepresented by the formula (I) of the present invention, and in eachreaction in the synthesis of raw material compounds, when reactivegroups such as a hydroxyl group (an alcoholic hydroxyl group, a phenolichydroxyl group, a heterocyclic hydroxyl group, etc.), an amino group, acarboxy group, and a thiol group are used as substituents, it is alsopossible to appropriately protect these groups in each reaction step,and then to remove the protective groups at a suitable stage.

Examples of the protective groups for the hydroxyl group (an alcoholichydroxyl group, a phenolic hydroxyl group, a heterocyclic hydroxylgroup, etc.) that can be used herein include: C₁₋₆ alkyl groupsincluding, as representative examples, methyl, ethyl, n-propyl,isopropyl, n-butyl, and tert-butyl; alkoxylalkyl groups including, asrepresentative examples, methoxymethyl (MOM) and methoxyethoxymethyl(MEM); tetrahydropyranyl (THP) groups; aralkyl groups including, asrepresentative examples, benzyl (Bn) and triphenylmethyl (Tr); silylgroups including, as representative examples, trimethylsilyl (TMS),triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), andt-butyldiphenylsilyl (TBDPS); alkanoyl groups including, asrepresentative examples, acetyl (Ac), ethylcarbonyl, and pivaloyl (Piv);aralkylcarbonyl groups including, as a representative example,benzylcarbonyl; aroyl groups including, as a representative example,benzoyl (Bz); alkoxylcarbonyl groups including, as representativeexamples, methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl (Boc);and aralkyloxycarbonyl groups including as a representative example,benzyloxycarbonyl (Z).

Examples of the protective groups for the amino group (—NH₂ group) orthe imino group (—NH— group) that can be used herein include: alkanoylgroups including, as representative examples, acetyl (Ac),ethylcarbonyl, and pivaloyl (Piv); alkoxylcarbonyl groups including, asrepresentative examples, methoxycarbonyl, ethoxycarbonyl, andt-butoxycarbonyl (Boc); allyloxycarbonyl (Alloc) groups;fluorenylmethoxycarbonyl (Fmoc) groups; phenyloxycarbonyl;aralkyloxycarbonyl groups including, as representative examples,benzyloxycarbonyl (Z), p-methoxybenzyloxycarbonyl, andp-nitrobenzyloxycarbonyl; aralkyl groups including, as representativeexamples, benzyl (Bn) and triphenylmethyl (Tr); aroyl groups includingas a representative example, benzoyl (Bz); aralkylcarbonyl groupsincluding as a representative example, benzylcarbonyl; sulfonyl groupsincluding, as representative examples, methanesulfonyl (Ms),p-toluenesulfonyl (Ts), 2,4-dinitrobenzenesulfonyl (Nos), andbenzenesulfonyl (Bs); 2-(trimethylsilyl)ethoxymethyl (SEM) groups;phthaloyl (Pht) groups; and N,N-dimethylaminomethylene groups.

Examples of the protective groups for the carboxy group (—COOH group)that can be used herein include: alkyl groups including, asrepresentative examples, methyl, ethyl, n-propyl, isopropyl, n-butyl,and tert-butyl; alkenyl groups including, as a representative example,allyl; aryl groups including, as a representative example, phenyl (Ph);aralkyl groups including, as representative examples, benzyl (Bn) andtriphenylmethyl (Tr); and silyl groups including, as representativeexamples, trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), and t-butyldiphenylsilyl (TBDPS).

Examples of the protective groups for the thiol group (—SH group) thatcan be used herein include: alkyl group including, as representativeexamples, methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl;aralkyl groups including, as representative examples, benzyl (Bn) andtriphenylmethyl (Tr); alkanoyl groups including, as representativeexamples, acetyl (Ac), ethylcarbonyl, and pivaloyl (Piv); and aroylgroups including, as a representative example, benzoyl (Bz).

A method for introducing and/or removing such protective groups can becarried out, as appropriate, depending on the type of a group to beprotected or a protective group. Introduction and/or removal ofprotective groups can be carried out according to the method described,for example, in Greene et al., “Protective Groups in Organic Synthesis,4^(th) edition, 2007, John Wiley & Sons.”

When the protective groups are acyl type protective groups such as:alkanoyl groups including, as representative examples, acetyl (Ac),ethylcarbonyl, and pivaloyl (Piv); alkoxylcarbonyl groups including, asrepresentative examples, methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl (Boc); and aroyl groups including, as a representativeexample, benzoyl (Bz), as a method for removing the protective groups,the protected group is hydrolyzed using a suitable base such as analkali metal hydroxide including lithium hydroxide, sodium hydroxide, orpotassium hydroxide, so that the protective group can be removed.

When the protective groups are: alkoxylalkyl type protective groupsincluding, as representative examples, methoxymethyl (MOM),methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP); alkoxylcarbonyltype protective groups including, as a representative example,t-butoxycarbonyl (Boc); aralkyloxycarbonyl type protective groupsincluding, as representative examples, benzyloxycarbonyl (Z) andp-methoxybenzyloxycarbonyl; or silyl type protective groups including,as representative examples, trimethylsilyl (TMS), triethylsilyl (TES),and t-butyldimethylsilyl (TBDMS), suitable acids such as acetic acid,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,trifluoroacetic acid, or trifluoromethanesulfonic acid, or a combinationof these acids are used to remove the protective groups.

Moreover, the above described silyl type protective groups can also beremoved using suitable fluoride ion (F⁻) generation reagents, such astetrabutyl ammonium fluoride or hydrogen fluoride.

Aralkyloxycarbonyl groups including, as representative examples,benzyloxycarbonyl (Z), p-methoxybenzyloxycarbonyl, andp-nitrobenzyloxycarbonyl, and aralkyl groups including, as arepresentative example, benzyl (Bn), can be removed by hydrolysis using,for example, a palladium-carbon (Pd—C) catalyst.

Furthermore, the above described benzyl group can also be removed byBirch reduction using metallic sodium in liquid ammonia.

The triphenylmethyl (Tr) group can be removed by using a suitable acidsuch as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid,or using a combination of these acids. Further, the protective group canalso be removed by Birch reduction using metallic sodium or metalliclithium in liquid ammonia, or by hydrolysis using a palladium carboncatalyst.

The sulfonyl (—SO₂—) group can be removed, for example, by performingone-electron reduction using Na/anthracene or Na/naphthalene at a lowtemperature, or by performing Birch reduction using metallic sodium ormetallic lithium in liquid ammonia.

Moreover, among the sulfonyl groups, a 2-nitrobenzenesulfonyl (Ns) groupcan be removed under mild conditions in which, for example, it isreacted with thiol in the presence of a basic reagent such as potassiumcarbonate or triethylamine

The above described methods for removing protective groups are providedfor illustrative purpose only. Deprotection can be carried out, forexample, by applying the method described in Greene et al., “ProtectiveGroups in Organic Synthesis, 4th edition, 2007, John Wiley & Sons,” orvarious types of published study papers.

Reaction conditions applied to the below-mentioned production methodsare determined as follows, unless otherwise specified. That is, thereaction temperature is in a range from −78° C. to a temperature atwhich a solvent is refluxed. When the temperature is not particularlydescribed, it is room temperature (0° C. to 35° C.). The reaction timeis a period of time in which the reaction sufficiently progresses.

Moreover, the reaction in each step of the production method can becarried out in the absence of a solvent, or after raw material compoundshave been dissolved or suspended in a suitable solvent that isirrelevant to the reaction. Specific examples of such a solvent that isirrelevant to the reaction include: water; saturated hydrocarbonsolvents such as cyclohexane and hexane; aromatic hydrocarbon solventssuch as benzene, chlorobenzene, toluene, and xylene; alcohol solventssuch as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,and 2-methoxyethanol; polar amide solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, and 1,3-dimethyl-2-imidazolidinone; sulfoxide solvents such asdimethyl sulfoxide; nitrile solvents such as acetonitrile andpropionitrile; ether solvents such as diethyl ether, diisopropyl ether,diphenyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;ester solvents such as methyl acetate, ethyl acetate, and butyl acetate;ketone solvents such as acetone and methyl ethyl ketone; halogenatedhydrocarbon solvents such as dichloromethane, chloroform, carbontetrachloride, and 1,2-dichloroethane; basic solvents such astriethylamine, N,N-diisopropylethylamine, pyridine, and lutidine; acidanhydrides such as acetic anhydride; organic acids such as formic acid,acetic acid, propionic acid, trifluoroacetic acid, and methanesulfonicacid; and inorganic acids such as hydrochloric acid and sulfuric acid. Asingle type of solvent may be used alone, or two or more types ofsolvents may appropriately be selected depending on reaction conditions,and may be then mixed at an appropriate ratio before use.

Specific examples of the base (or deoxidizer) used in the method forproducing the compound in the present invention include inorganic basessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide,magnesium hydroxide, lithium carbonate, sodium carbonate, potassiumcarbonate, cesium carbonate, calcium carbonate, and sodium hydrogencarbonate; organic bases such as triethylamine,N,N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine,pyridine, lutidine, 4-dimethylaminopyridine(DMAP), N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]-7-undecene, and imidazole; metal alkoxides suchas sodium methoxide, sodium ethoxide, potassium tert-butoxide, andsodium tert-butoxide; alkali metal hydrides such as sodium hydride andpotassium hydride; metal amides such as sodium amide, lithiumdiisopropyl amide, and lithium hexamethyl disilazide; and organiclithium reagents such as methyl lithium, n-butyl lithium, sec-butyllithium, and tert-butyl lithium. Moreover, specific examples of the acidor acid catalyst used in the method for producing the compound in thepresent invention include: inorganic acids such as hydrochloric acid,sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid;organic acids such as acetic acid, trifluoroacetic acid, oxalic acid,phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid,succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and10-camphor-sulfonic acid; and Lewis acids such as a boron trifluorideether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zincchloride, and anhydrous iron chloride. However, examples are notnecessarily limited thereto.

The salt of the formula (I) can be produced according to a known method.For example, when the compound of the formula (I) is a basic compound,the salt thereof can be produced by adding an inorganic acid (mineralacid) such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, or phosphoric acid, or an organic acid such as formic acid, aceticacid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid,to the compound. When the compound of the formula (I) is an acidiccompound, the salt thereof can be produced by adding an organic basesuch as ammonia, trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine,N,N′-dibenzylethylenediamine, or N,N-dialkylaniline, or an inorganicbase such as lithium carbonate, sodium carbonate, potassium carbonate,cesium carbonate, lithium hydroxide, sodium hydroxide, potassiumhydroxide, or sodium hydrogen carbonate, to the compound.

The compound represented by the formula (I) of the present invention canbe obtained by a condensation reaction of a carboxylic acid derivativerepresented by a formula (CA) [wherein it is a carboxylic acid of aformula (CA-1), when L′═OH; it is a carboxylate of a formula (CA-2),when L′=OM; and it is an acid halide of a formula (CA-3), when L′═X]with amine represented by a formula (AM).

Hereinafter, methods for producing the compounds represented by theformula (CA), the formula (AM), and the formula (I) will be described.

<Production Method A>

Method for producing a carboxylic acid derivative represented by theformula (CA) [wherein it is a carboxylic acid of the formula (CA-1),when L′=OH; it is a carboxylate of the formula (CA-2), when L′=OM; andit is an acid halide of the formula (CA-3), when L′=X]:

<Step 1> <Case of W=Boronic Acid Ester>

Using the compound represented by the formula (A-1), a reaction iscarried out according to a known method, for example, the methoddescribed in “The Journal of Organic Chemistry, 60, 7508-2665, 1995,” ina temperature range from 0° C. to a temperature at which a solvent isrefluxed, using a solvent irrelevant to the reaction, such as toluene,N,N-dimethylformamide, dimethyl sulfoxide, or 1,4-dioxane, or using amixed solvent thereof, in the presence of a diboron ester such asbis(pinacolato)diboron or bis(neopentylglycolato)diboron, in thepresence of a palladium catalyst such as palladium acetate (II),tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethanecomplex, in the presence or absence of a phosphine reagent such astriphenylphosphine, tris(tert-butyl)phosphine, tris(o-tolyl)phosphine,or 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, and an organic orinorganic base such as triethylamine, N,N-diisopropylethylamine,potassium carbonate, or potassium acetate, or in the presence or absenceof tetramethylammonium chloride, tetrabutylammonium chloride, etc.,which is used instead of the phosphine reagent, so as to produce theboronic acid ester represented by the formula (A-2).

<Case of W=Boronic Acid>

Using the compound represented by the formula (A-1), according to aknown method, for example, the method described in “Chemische Berichte,42, 3090, 1909,” trialkyl borate such as trimethyl borate ortriisopropyl borate is added to a solvent irrelevant to the reaction,such as toluene, tetrahydrofuran, or 1,4-dioxane, or to a mixed solventthereof, in the presence of alkyl lithium such as n-butyllithium orsec-butyllithium, a Grignard reagent such as isopropyl magnesiumchloride, or metallic magnesium, and a reaction is then carried out in atemperature range from −78° C. to room temperature. Thereafter, an acidsuch as hydrochloric acid or sulfuric acid is added to the reactionsolution, and the reaction is then carried out in a temperature rangefrom 0° C. to a temperature at which a solvent is refluxed, so as toproduce the boronic acid represented by the formula (A-2).

<Case of W=Trifluoroborate>

Using the boronic acid ester or boronic acid represented by the formula(A-1), a reaction is carried out according to a known method, forexample, the method described in “Chemical Reviews, 108, 288-325, 2008,”in a temperature range from 0° C. to a temperature at which a solvent isrefluxed, using a solvent irrelevant to the reaction, such as methanol,ethanol, or water, or using a mixed solvent thereof, in the presence ofpotassium hydrogen difluoride (KHF₂), so as to produce thetrifluoroborate represented by the formula (A-2).

<Case of W=N-Methyliminodiacetic Acid (MIDA) Borate>

Using the boronic acid represented by the formula (A-1), a reaction iscarried out according to a known method, for example, the methoddescribed in “Journal of Organometallic Chemistry, 307 (1), pp. 1-6,1986,” in a temperature range from 0° C. to a temperature at which asolvent is refluxed, using a solvent irrelevant to the reaction, such asbenzene, toluene, xylene, or dimethyl sulfoxide, or using a mixedsolvent thereof, in the presence of N-methyliminodiacetic acid (MIDA),so as to produce an N-methyliminodiacetic acid (MIDA) borate representedby the formula (A-2).

<Step 2>

Using the compound represented by the formula (A-2) obtained in<Production Method A> <Step 1> and the halogenated heteroaryl derivativerepresented by the formula (A-3), a reaction is carried out according toa known method, for example, the methods described in “Jikken KagakuKoza, 5^(th) edition, 18, Organic Compound Synthesis VI-OrganicSynthesis using Metal-, pp. 327-352, 2004, Maruzen,” and “Journal ofMedicinal Chemistry, 48 (20), pp. 6326-6339, 2005,” in a temperaturerange from 0° C. to a temperature at which a solvent is refluxed, usinga solvent irrelevant to the reaction, such as toluene, xylene,N,N-dimethylformamide, N,N-dimethylacetamide, dimethoxyethane,acetonitrile (acetonitrile/water), 1,4-dioxane (1,4-dioxane/water), ortetrahydrofuran (tetrahydrofuran/water), or using a mixed solventthereof, in the presence of a palladium catalyst such as palladiumacetate (II) (Pd(OAc)₂), tetrakis(triphenyl phosphine)palladium(Pd(PPh₃)₄), tris(dibenzylidene acetone)dipalladium((dba)₃Pd₂),bis(dibenzylidene acetone)palladium((dba)₂Pd), or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂), a phosphinereagent such as triphenyl phosphine, tris(tert-butyl)phosphine,tris(o-tolyl)phosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,or 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and an organicor inorganic base such as triethylamine, N,N-diisopropylethylamine,potassium phosphate, potassium carbonate, or cesium carbonate, so as toproduce a compound represented by the formula (A-4). Otherwise, usingtetramethylammonium chloride, tetrabutylammonium chloride, or the like,instead of the phosphine reagent, the compound represented by theformula (A-4) can be produced by the same method as described above.

<Step 3>

<Case of R^(A)=C₁₋₆ Alkyl Group (e.g. Methyl and Ethyl Group) or C₆₋₁₄Aryl Group (e.g. Phenyl Group)>

Using the compound represented by the formula (A-4) obtained in<Production Method A> <Step 2>, a reaction is carried out according to aknown method, for example, the method described in “Jikken Kagaku Koza,4^(th) edition, 22, Organic Synthesis IV, Acid, Amino Acid, and Peptide,pp. 1-43, 1992, Maruzen,” in a temperature range from 0° C. to atemperature at which a solvent is refluxed, using a solvent inactive tothe reaction, such as water, methanol, ethanol, 2-propanol,N,N-dimethylformamide, 1,4-dioxane, or tetrahydrofuran, or using a mixedsolvent thereof, in the presence of a base such as lithium hydroxide,sodium hydroxide, potassium hydroxide, lithium carbonate, sodiumcarbonate, or potassium carbonate, so as to produce a compoundrepresented by the formula (CA-1) or the formula (CA-2), depending on adifference in a post-treatment step after completion of the reaction.

<Case of R^(A)=Tert-Butyl Group>

Using the compound represented by the formula (A-4) obtained in<Production Method A> <Step 2>, the compound is reacted with an acidsuch as hydrochloric acid or trifluoroacetic acid to produce thecompound represented by the formula (CA-1).

<Case of R^(A)=C₇₋₂₀ Aralkyl Group (e.g. Benzyl Group)>

Using the compound represented by the formula (A-4) obtained in<Production Method A> <Step 2>, a reaction is carried out according to aknown method, for example, the method described in “Jikken Kagaku Koza,4^(th) edition, 26, Organic Synthesis VIII, Asymmetric Synthesis,Reduction, Sugar, and Labeling Compound, pp. 159-266, 1992, Maruzen,” ina temperature range from 0° C. to a temperature at which a solvent isrefluxed, using a solvent irrelevant to the reaction, such as an alcoholsolvent such as methanol, ethanol, or 2-propanol, or an ether solventsuch as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or1,4-dioxane, or a polar solvent such as ethyl acetate or methyl acetate,or using a mixed solvent thereof, in the presence of a catalyst such aspalladium-carbon (Pd—C), Raney nickel (Raney-Ni), or platinum oxide(Pt₂O), in a hydrogen gas atmosphere, so as to produce the compoundrepresented by the formula (CA-1).

<Step 4>

Using the compound represented by the formula (CA-2) obtained in<Production Method A> <Step 3>, a reaction is carried out according to aknown method, for example, the method described in “Journal of theAmerican Chemical Society, 109 (24), pp. 7488-7494, 1987,” in atemperature range from 0° C. to a temperature at which a solvent isrefluxed, using a halogenating agent such as thionyl chloride, oxalylchloride, phosphoryl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus pentachloride, or phosphorus tribromide, andusing a solvent inactive to the reaction, such as dioxane,tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane,or chloroform, or using a mixed solvent thereof, in the presence orabsence of a base such as triethylamine, N,N-diisopropylethylamine, orN,N-dimethylaminopyridine, so as to produce the compound represented bythe formula (CA-3).

<Production Method B>

Methods for producing amines represented by a formula (AM-1) and aformula (AM-2): Case in which a fused ring B is animidazo[1,2-a]pyridine ring (formula (AM-1)) or a5,6,7,8-tetrahydroimidazo[1,2-a]pyridine ring (formula (AM-2)):

<Step 1>

Using the compound represented by the formula (B-1) and the compoundrepresented by the formula (B-2), a reaction is carried out according toa known method, for example, the method described in “European Journalof Medicinal Chemistry, 52, pp. 137-150, 2012,” in a temperature rangefrom 0° C. to a temperature at which a solvent is refluxed, using asolvent inactive to the reaction, such as methanol, ethanol, or2-propanol, or using a mixed solvent thereof, so as to produce acompound represented by the formula (B-3).

<Step 2>

Using the compound represented by the formula (B-3) obtained in<Production Method B> <Step 1>, a reaction is carried out according to<Production Method A> <Step 3>, so as to produce the compoundrepresented by the formula (B-4).

<Step 3>

Using the compound represented by the formula (B-4) obtained in<Production Method B> <Step 2>, a reaction is carried out according to aknown method, for example, the method described in “StrategicApplications of Named Reactions in Organic Synthesis, Elsevier AcademicPress, 2005, pp. 116-117, Curtius Rearrangement,” in a temperature rangefrom 0° C. to a temperature at which a solvent is refluxed, using asolvent inactive to the reaction, such as toluene or benzene, or using amixed solvent thereof, and using diphenylphosphoryl azide (DPPA), in thepresence of a base such as triethylamine. Thereafter, the resultingcompound is reacted with alcohol such as methanol, ethanol, tert-butylalcohol, or benzyl alcohol, so as to produce the compound represented bythe formula (B-5).

<Step 4>

Using the compound represented by the formula (B-5) obtained in<Production Method B> <Step 3>, the compound is reacted with aprotective group (—COOR^(A)) by a method that depends on the type of theprotective group, according to a known method, for example, the methoddescribed in “Protective Groups in Organic Synthesis 4^(th) edition,2007, John Wiley & Sons, Greene et al.,” so as to produce the compoundrepresented by the formula (AM-1), from which the —COOR^(A) group isremoved.

<Step 5>

Using the compound represented by the formula (AM-1) obtained in<Production Method B> <Step 4>, a reaction is carried out according to aknown method, for example, the method described in “Journal of MedicinalChemistry, 48 (10), pp. 3586-3640, 2005,” in a temperature range from 0°C. to a temperature at which a solvent is refluxed, using a solventirrelevant to the reaction, such as an alcohol solvent such as methanol,ethanol, or 2-propanol, or an ether solvent such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, or a polar solventsuch as ethyl acetate or methyl acetate, or using a mixed solventthereof, in the presence of concentrated hydrochloric acid, in thepresence of a catalyst such as platinum oxide (Pt₂O), and in a hydrogengas atmosphere, so as to produce the compound represented by the formula(AM-2).

<Production Method C>

Alternative method for producing amine represented by the formula (AM-2)[the case of R⁴=C₆₋₁₄ aryl group] and method for producing aminerepresented by the formula (AM-3):

<Step 1>

Using the compound represented by the formula (B-1) and the compoundrepresented by the formula (C-1), a reaction is carried out according to<Production Method B> <Step 1>, so as to produce the compoundrepresented by the formula (C-2).

<Step 2>

Using the compound represented by the formula (C-2) obtained in<Production Method C> <Step 1>, a reaction can be carried out accordingto <Production Method B> <Step 5>, so as to produce the compoundrepresented by the formula (C-3).

<Step 3>

Using the compound represented by the formula (C-3) obtained in<Production Method C> <Step 2> and N-bromosuccinimide (NBS), a reactionis carried out according to a known method, for example, the methoddescribed in “Journal of Heterocyclic Chemistry, 39 (4), pp. 733-735,2002,” in a temperature range from 0° C. to a temperature at which asolvent is refluxed, using a solvent irrelevant to the reaction, such asa halogenated solvent such as dichloromethane, chloroform, or1,2-dichloroethane, or using a mixed solvent thereof, in the presence ofa base such as sodium hydrogen carbonate, sodium carbonate, potassiumhydrogen carbonate, or potassium carbonate, so as to produce thecompound represented by the formula (C-4).

<Step 4>

Using the compound represented by the formula (C-4) obtained in<Production Method C> <Step 3> and isopropyl magnesium chloride, areaction is carried out according to a known method, for example, themethod described in “International Publication WO2007/121390,” in atemperature range from −30° C. to a temperature at which a solvent isrefluxed, using a solvent irrelevant to the reaction, such as ether,tetrahydrofuran, dioxane, or 1,2-dimethoxyethane, or using a mixedsolvent thereof, so as to produce the compound represented by theformula (C-5).

<Step 5>

Using the compound represented by the formula (C-5) obtained in<Production Method C> <Step 4>, a reaction is carried out according to<Production Method A> <Step 3>, so as to produce the compoundrepresented by the formula (C-6).

<Step 6>

Using the compound represented by the formula (C-6) obtained in<Production Method C> <Step 5>, a reaction is carried out according to<Production Method B> <Step 3>, so as to produce the compoundrepresented by the formula (C-7).

<Step 7>

Using the compound represented by the formula (C-7) obtained in<Production Method C> <Step 6> and the boranic acid derivativerepresented by the formula (C-8), a reaction is carried out according to<Production Method A> <Step 2>, so as to produce the compoundrepresented by the formula (C-9).

<Step 8>

Using the compound represented by the formula (C-9) obtained in<Production Method C> <Step 7>, a reaction is carried out according to<Production Method B> <Step 4>, so as to produce the compoundrepresented by the formula (AM-2).

<Step 9>

Using the compound represented by the formula (C-7) obtained in<Production Method C> <Step 6>, a reaction is carried out according to<Production Method B> <Step 4>, so as to produce the compoundrepresented by the formula (AM-3).

<Production Method D>

Methods for producing amines represented by a formula (AM-4) and aformula (AM-5): Case in which a fused ring B is atriazolo[1,2-a]pyridine ring (formula (AM-4)) or a5,6,7,8-tetrahydrotriazolo[1,2-a]pyridine ring (formula (AM-5)):

<Step 1>

Using the compound represented by the formula (B-1) and thethioisocyanate compound represented by the formula (D-1), a reaction iscarried out according to a known method, for example, the methoddescribed in “The Journal of Organic Chemistry, 65 (5), pp. 1566-1568,2000,” in a temperature range from 0° C. to a temperature at which asolvent is refluxed, using a solvent irrelevant to the reaction, such asether, tetrahydrofuran, dioxane, or 1,2-dimethoxyethane, or using amixed solvent thereof, so as to produce the compound represented by theformula (D-2).

<Step 2>

Using the compound represented by the formula (D-2) obtained in<Production Method D> <Step 1> and hydroxylamine hydrochloride, areaction is carried out according to a known method, for example, themethod described in “Synthesis, (11), pp. 1649-1652, 2003,” in atemperature range from 0° C. to a temperature at which a solvent isrefluxed, using a solvent irrelevant to the reaction, such as methanol,ethanol, or 2-propanol, or using a mixed solvent thereof, so as toproduce the compound represented by the formula (D-3).

<Step 3>

Using the compound represented by the formula (D-3) obtained in<Production Method D> <Step 2>, isoamyl nitrile, and copper bromide(CuBr₂), a reaction is carried out according to a known method, forexample, the method described in “The Journal of Organic Chemistry, 42(14), pp. 2426-2431, 1977,” in a temperature range from 0° C. to atemperature at which a solvent is refluxed, using a solvent irrelevantto the reaction, such as acetonitrile, or using a mixed solvent thereof,so as to produce the compound represented by the formula (D-4).

<Step 4>

Using the compound represented by the formula (D-4) obtained in<Production Method D> <Step 3>, a reaction is carried out according to<Production Method A> <Step 3>, so as to produce the compoundrepresented by the formula (D-5).

<Step 5>

Using the compound represented by the formula (D-5) obtained in<Production Method D> <Step 4>, a reaction is carried out according to<Production Method B> <Step 3>, so as to produce the compoundrepresented by the formula (D-6).

<Step 6> <Case of R⁴=C₆₋₁₄ Aryl Group or 5- to 7-Membered MonocyclicHeteroaryl Group>

Using the compound represented by the formula (D-6) obtained in<Production Method D> <Step 5> and the boranic acid derivativerepresented by the formula (C-8), a reaction is carried out according to<Production Method A> <Step 2>, so as to produce the compoundrepresented by the formula (D-7).

<Case of R⁴=3- to 14-Membered Non-Aromatic Heterocyclic Group>

Using the compound represented by the formula (D-6) obtained in<Production Method D> <Step 5> and a non-aromatic heterocyclic compound(e.g. a 3- to 8-membered ring non-aromatic heterocyclic compound such asaziridine, pyrrolidine, piperazine, piperidine, or morpholine), areaction is carried out in the absence of a solvent at an outsidetemperature of approximately 100° C. to 150° C., so as to produce thecompound represented by the formula (D-7).

Alternatively, using the compound represented by the formula (D-6)obtained in <Production Method D> <Step 5> and a non-aromaticheterocyclic compound (e.g. a 3- to 8-membered ring non-aromaticheterocyclic compound such as aziridine, pyrrolidine, piperazine,piperidine, or morpholine), a reaction is carried out according to aknown method, for example, the method described in “Organic Synthesis,78, p. 23, 2002,” in a temperature range from 0° C. to a temperature atwhich a solvent is refluxed, using a solvent irrelevant to the reaction,such as toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide,dimethoxyethane, acetonitrile (acetonitrile/water), dioxane(dioxane/water), or tetrahydrofuran (tetrahydrofuran/water), or using amixed solvent thereof, in the presence of a Pd catalyst such astris(dibenzylideneacetone)dipalladium ((dba)₃Pd₂), a phosphine reagentsuch as 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (XANTPHOS),and an organic or inorganic base such as triethylamine,N,N-diisopropylethylamine, potassium phosphate, potassium carbonate, orcesium carbonate, so as to produce the compound represented by theformula (D-7).

<Step 7>

Using the compound represented by the formula (D-7) obtained in<Production Method D> <Step 6>, a reaction is carried out according to<Production Method B> <Step 4>, so as to produce the compoundrepresented by the formula (AM-4).

<Step 8>

Using the compound represented by the formula (D-7) obtained in<Production Method D> <Step 6>, a reaction is carried out according to<Production Method B> <Step 5>, so as to produce the compoundrepresented by the formula (D-8).

<Step 9>

Using the compound represented by the formula (D-8) obtained in<Production Method D> <Step 8>, a reaction is carried out according to<Production Method B> <Step 4>, so as to produce the compoundrepresented by the formula (AM-5).

<Step 10>

Using the compound represented by the formula (AM-4) obtained in<Production Method D> <Step 7>, a reaction is carried out according to<Production Method B> <Step 5>, so as to produce the compoundrepresented by the formula (AM-5).

<Production Method E>

Alternative method for producing compounds represented by formula (D-7)and formula (D-8) in <Production Method D> (wherein R⁴≠halogen atom).

<Step 1>

Using the compound represented by the formula (B-1) and the compoundrepresented by the formula (E-1), a reaction is carried out according toa known method, for example, the method described in “Journal ofHeterocyclic Chemistry, 12 (1), pp. 107-110, 1975,” in a temperaturerange from 0° C. to a temperature at which a solvent is refluxed, usinga solvent irrelevant to the reaction, such as methylene chloride orchloroform, or using a mixed solvent thereof, so as to produce thecompound represented by the formula (E-2).

<Step 2>

Using the compound represented by the formula (E-2) obtained in<Production Method E> <Step 1> and the compound represented by theformula (E-3) (wherein Y=H, OH, OR^(A), or Cl), a reaction is carriedout according to a known method, for example, the method described in“Journal of Heterocyclic Chemistry, 12 (1), pp. 107-110, 1975.” In thecase of <Y=OR^(A), H, or Cl>, the reaction is carried out in atemperature range from 0° C. to a temperature at which a solvent isrefluxed, using a solvent irrelevant to the reaction that is selectedfrom among methylene chloride, chloroform, acetonitrile, methanol,N-methylpyrrolidone and the like, or using a mixed solvent thereof, inthe presence of a base such as sodium hydroxide or sodium methoxide, soas to produce the compound represented by the formula (E-4). In the caseof <Y=OH>, the reaction is carried out in a temperature range from 0° C.to a temperature at which a solvent is refluxed, in a solvent irrelevantto the reaction, such as a halogenated solvent such as dichloromethaneor chloroform, an ether solvent such as diethyl ether ortetrahydrofuran, an aromatic hydrocarbon solvent such as toluene orbenzene, a polar solvent such as N,N-dimethylformamide, or an alcoholsolvent such as methanol, ethanol, or 2-propanol, in the presence of acondenser such as 1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),1-hydroxybenzotriazole (HOBT),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl),2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), or4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), and in the presence or absence of a base such as triethylamineor pyridine, so as to produce the compound represented by the formula(E-4).

<Step 3>

Using the compound represented by the formula (E-4) obtained in<Production Method E> <Step 2>, a reaction is carried out according to<Production Method A> <Step 3>, so as to produce the compoundrepresented by the formula (E-5).

<Step 4>

Using the compound represented by the formula (E-5) obtained in<Production Method E> <Step 3>, a reaction is carried out according to<Production Method B> <Step 3>, so as to produce the compoundrepresented by the formula (D-7).

<Step 5>

Using the compound represented by the formula (E-4) obtained in<Production Method E> <Step 2>, a reaction is carried out according to<Production Method B> <Step 5>, so as to produce the compoundrepresented by the formula (E-6).

<Step 6>

Using the compound represented by the formula (E-6) obtained in<Production Method E> <Step 5>, a reaction is carried out according to<Production Method A> <Step 3>, so as to produce the compoundrepresented by the formula (E-7).

<Step 7>

Using the compound represented by the formula (E-7) obtained in<Production Method E> <Step 6>, a reaction is carried out according to<Production Method B> <Step 3>, so as to produce the compoundrepresented by the formula (D-8).

<Step 8>

Using the compound represented by the formula (E-5) obtained in<Production Method E> <Step 3>, a reaction is carried out according to<Production Method B> <Step 5>, so as to produce the compoundrepresented by the formula (E-7).

<Step 9>

Using the compound represented by the formula (D-7) obtained in<Production Method E> <Step 4>, the same reaction as that in <ProductionMethod D> <Step 8> is carried out, so as to produce the compoundrepresented by the formula (D-8).

<Production Method F>

Method for producing amine represented by formula (AM-6): the synthesisof an imidazolo[1,2-a]pyridine ring (AM-6) in a case in which Z=CR⁵ andR⁵=a halogen atom in the fused ring B (wherein R⁴≠a halogen atom):

<Step 1>

Using the compound represented by the formula (B-1) and the compoundrepresented by the formula (F-1), a reaction is carried out according toa known method, for example, the method described in “Russian ChemicalBulletin, 54, 470, 2005,” in a temperature range from 0° C. to atemperature at which a solvent is refluxed, using a pyridine solvent inthe presence of thionyl chloride, so as to produce the compoundrepresented by the formula (F-2).

<Step 2>

Using the compound represented by the formula (F-2) obtained in<Production Method F> <Step 1>, a reaction is carried out according to aknown method, for example, the method described in “Russian ChemicalBulletin, 54, 470, 2005,” in a temperature range from 0° C. to atemperature at which a solvent is refluxed, using N-methyl-2-pyrrolidoneas a solvent in the presence of trimethyl phosphite, so as to producethe compound represented by the formula (F-3).

<Step 3>

Using the compound represented by the formula (F-3) obtained in<Production Method F> <Step 2>, a reaction is carried out according to<Production Method A> <Step 3>, so as to produce the compoundrepresented by the formula (F-4).

<Step 4>

Using the compound represented by the formula (F-4) obtained in<Production Method F> <Step 3>, a reaction is carried out according to<Production Method B> <Step 3>, so as to produce the compoundrepresented by the formula (F-5).

<Step 5>

Using the compound represented by the formula (F-5) obtained in<Production Method F> <Step 4>, a reaction is carried out according to<Production Method B> <Step 4>, so as to produce the compoundrepresented by the formula (AM-6).

<Production Method G>

Method for producing compound represented by formula (I): a condensationreaction of an amine represented by a formula (AM) with carboxylic acidderivatives represented by a formula (CA-1), a formula (CA-2), and aformula (CA-3).

<Step 1>

The ester represented by the formula (A-4) is converted to a carboxylate(CA-2) by the method described in <Production Method A> <Step 3>.Thereafter, using the amine represented by the formula (AM), a reactionis carried out according to a known method, for example, the methoddescribed in “Jikken Kagaku Koza, 4^(th) edition, 22, Organic SynthesisIV, Acid, Amino Acid, and Peptide, pp. 191-309, 1992, Maruzen,” in atemperature range from 0° C. to a temperature at which a solvent isrefluxed, in a solvent irrelevant to the reaction, such as a halogenatedsolvent such as dichloromethane or chloroform, an ether solvent such asdiethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent suchas toluene or benzene, a polar solvent such as N,N-dimethylformamide, oran alcohol solvent such as methanol, ethanol, or 2-propanol, in thepresence of a condenser such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU), and in the presence or absenceof a base such as N,N-diisopropylethylamine, triethylamine, or pyridine,so as to produce the compound represented by the formula (I).

<Step 2>

Using the carboxylic acid represented by the formula (CA-1) and theamine represented by the formula (AM), a reaction is carried outaccording to a known method, for example, the method described in“Jikken Kagaku Koza, 4^(th) edition, 22, Organic Synthesis IV, Acid,Amino Acid, and Peptide, pp. 191-309, 1992, Maruzen,” in a temperaturerange from 0° C. to a temperature at which a solvent is refluxed, in asolvent irrelevant to the reaction, such as a halogenated solvent suchas dichloromethane or chloroform, an ether solvent such as diethyl etheror tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene orbenzene, a polar solvent such as N,N-dimethylformamide, or an alcoholsolvent such as methanol, ethanol, or 2-propanol, in the presence of acondenser such as 1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),1-hydroxybenzotriazole (HOBT),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl),2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), polyphosphoric acid (PPA), or2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU), and in the presence or absenceof a base such as triethylamine, N,N-diisopropylethylamine, or pyridine,so as to produce the compound represented by the formula (I).

Otherwise, as an alternative method, using the carboxylic acidrepresented by the formula (CA-1) and the amine represented by theformula (AM), a reaction is carried out according to a known method, forexample, the method described in “International Publication No.WO2005/034867” or “Bioorganic & Medicinal Chemistry Letters, 14 (4), pp.983-988, 2004,” in a temperature range from 0° C. to a temperature atwhich a solvent is refluxed, in a solvent irrelevant to the reaction,such as pyridine, in the presence of phosphoryl chloride, so as toproduce the compound represented by the formula (I).

<Step 3>

Using the acid halide represented by the formula (CA-3) and the aminerepresented by the formula (AM), a reaction is carried out according toa known method, for example, the method described in “Jikken KagakuKoza, 4^(th) edition, 22, Organic Synthesis IV, Acid, Amino Acid, andPeptide, pp. 144-146, 1992, Maruzen,” in a temperature range from 0° C.to a temperature at which a solvent is refluxed, in a solvent irrelevantto the reaction, such as a halogenated solvent such as dichloromethane,chloroform, or 1,2-dichloroethane, an ether solvent such as diethylether, tetrahydrofuran, or 1,4-dioxane, an aromatic hydrocarbon solventsuch as toluene or benzene, or a polar solvent such asN,N-dimethylformamide, in the presence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine, or 4-dimethylaminopyridine, so asto produce the compound represented by the formula (I).

<Production Method H>

Method for producing compound represented by formula (I): a syntheticmethod from formula (I′″) (in case of R⁴=halogen) to formula (I).

<Case of R⁴=a C₆₋₁₄ Aryl Group or a 5- to 7-Membered MonocyclicHeteroaryl Group>

Using the compound represented by the formula (I′″) and the boranic acidderivative represented by the formula (C-8), a reaction is carried outaccording to <Production Method A> <Step 2>, so as to produce thecompound represented by the formula (I).

<Case of R⁴=a 3- to 14-Membered Non-Aromatic Heterocyclic Group>

Using the compound represented by the formula (I′″) and a non-aromaticheterocyclic compound (e.g. a 3- to 8-membered ring non-aromaticheterocyclic compound such as aziridine, pyrrolidine, piperazine,piperidine, or morpholine), a reaction is carried out according to<Production Method D> <Step 6> <Case of R⁴=a 3- to 14-memberednon-aromatic heterocyclic group>, so as to produce the compoundrepresented by the formula (I).

<Production Method I>

Method for producing compound represented by formula (I): a methodcomprising performing a condensation reaction between an aminerepresented by a formula (AM) and carboxylic acid derivativesrepresented by a formula (CA-1-2), a formula (CA-2-2), and a formula(CA-3-2), and then introducing Het that corresponds to a ring A portioninto the reaction product.

<Step 1>

The ester represented by the formula (A-4-2) is converted to thecarboxylate represented by the formula (CA-2-2) by performing a reactionaccording to <Production Method A> <Step 3>. Thereafter, using the aminerepresented by the formula (AM), a reaction is carried out according to<Production Method G> <Step 1>, so as to produce the compoundrepresented by the formula (I′″-2).

<Step 2>

Using the carboxylic acid represented by the formula (CA-1-2) and theamine represented by the formula (AM), a reaction is carried outaccording to <Production Method G> <Step 2>, so as to produce thecompound represented by the formula (I′″-2).

<Step 3>

Using the acid halide represented by the formula (CA-3-2) and the aminerepresented by the formula (AM), a reaction is carried out according to<Production Method G> <Step 3>, so as to produce the compoundrepresented by the formula (I′″-2).

<Step 4>

Using the compound represented by the formula (I′″-2) obtained in<Production Method I> <Step 1>, or <Production Method I> <Step 2>, or<Production Method I> <Step 3>, a reaction is carried out according to<Production Method A> <Step 1>, so as to produce the compoundrepresented by the formula (I′″-3).

<Step 5>

Using the compound represented by the formula (I′″-3) obtained in<Production Method I> <Step 4> and the compound represented by theformula (A-3), a reaction is carried out according to <Production MethodA> <Step 2>, so as to produce the compound represented by the formula(I).

<Production Method J>

Alternative method for producing compound represented by formula (I′″-3)in <Production Method I>.

<Step 1>

The ester represented by the formula (A-4-3) is converted to thecarboxylate represented by the formula (CA-2-3) by performing a reactionaccording to <Production Method A> <Step 3>. Thereafter, using the aminerepresented by the formula (AM), a reaction is carried out according to<Production Method G> <Step 1>, so as to produce the compoundrepresented by the formula (I′″-3).

<Step 2>

Using the carboxylic acid represented by the formula (CA-1-3) and theamine represented by the formula (AM), a reaction is carried outaccording to <Production Method G> <Step 2>, so as to produce thecompound represented by the formula (I′″-3).

<Step 3>

Using the acid halide represented by the formula (CA-3-3) and the aminerepresented by the formula (AM), a reaction is carried out according to<Production Method G> <Step 3>, so as to produce the compoundrepresented by the formula (I″-3).

[Combination Agent Containing the Compound in the Present Invention]

The compound or pharmaceutical composition of the present invention canbe used in combination with other drugs or agents according to a commonmethod applied in medical sites. Examples of a drug that can be used incombination with the compound in the present invention include (A)therapeutic agents for mental diseases, and in particular,schizophrenia, or for bipolar disorder, obsessive-compulsive disorder,major depression, Parkinson's disease, Huntington's disease, Alzheimer'sdisease, cognitive function disorder and defect of memory, and (B)therapeutic agents for diseases occurring together with schizophrenia.

Examples of the above described agent (A) include (1) atypicalantipsychotic agents [specifically, olanzapine, quetiapine, clozapine,ziprasidone, risperidone, paliperidone, perospirone, blonanserin,lurasidone, aripiprazole, sertindole, amisulpride, iloperidone,bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (2)typical antipsychotic agents [specifically, chlorpromazine,prochlorperazine, perphenazine, levomepromazine, fluphenazine,thioridazine, propericiazine, spiperone, moperone, haloperidol,timiperone, bromperidol, pimozide, floropipamide, sulpiride, tiapride,sultopride, nemonapride, oxypertine, etc.], (3) selective serotoninreuptake inhibitors (SSRI) [specifically, escitalopram, citalopram,paroxetine, sertraline, fluvoxamine, fluoxetine, etc.], (4) selectiveserotonin/noradrenalin reuptake inhibitors (SNRT) [specifically,milnacipran, duloxetine, venlafaxine, nefazodone, etc.], (5) selectivenoradrenalin/dopamine reuptake inhibitors (NDRI) [specifically,bupropion etc.], (6) noradrenergic and specific serotonergicantidepressants (NaSSA) [specifically, mirtazapine etc.], (7)triazolopyridine antidepressants (SARI) [specifically, trazodone etc.],(8) tetracyclic antidepressants [specifically, setiptiline, mianserin,maprotiline, etc.], (9) tricyclic antidepressants [specifically,amitriptyline, trimipramine, imipramine, nortriptyline, clomipramine,lofepramine, amoxapine, dosulepin, etc.], (10) other antidepressants[specifically, NS-2359, Lu AA21004, DOV21947, etc.], (11) α7 nicotinereceptor agonists, (12) α7 nicotine receptor activity modulators, (13)α7 nicotine receptor partial modulators [specifically, SSR-180711,PNU-120596, etc.], (14) other PDE inhibitors [PDE1 inhibitor, PDE2inhibitor, PDE4 inhibitor, PDES inhibitor, PDE7 inhibitor, PDE9inhibitor, etc.], (15) NK2 antagonists, (16) NK3 antagonists, (17)muscarinic M1 acetylcholine receptor activity modulators, (18)muscarinic M2 acetylcholine receptor activity modulators, (19) adenosinereceptor modulators, (20) muscarinic M4 acetylcholine receptor activitymodulators, (21) muscarinic M5 acetylcholine receptor activitymodulators, (22) adenosine receptor modulators, (23) glycine transporter1 (GlyT1) inhibitors [specifically, ALX5407, SSR504734, etc.], (24)glutamate enhancers [specifically, ampakine], (25) NMDA receptorinhibitors [specifically, memantine hydrochloride etc.], (26) metabolicglutamate receptor modulators (mGlu) [specifically, CDPPB, MPEP, etc.],(27) anti-anxiety agents ((i) benzodiazepine anti-anxiety agents[specifically, chlordiazepoxide, diazepam, oxazolam, medazepam,cloxazolam, lorazepam, clorazepate dipotassium, prazepam, bromazepam,fludiazepam, mexazolam, alprazolam, flutoprazepam, flutazolam, ethylloflazepate, etc.], (ii) thienodiazepine anti-anxiety agents[specifically, etizolam, clotiazepam, etc.], and (iii) serotonin 5-HT1Aagonists [specifically, tandospirone etc.]), (28) sleep inducing drugs((i) benzodiazepine sleep inducing drugs [specifically, nitrazepam,estazolam, flurazepam hydrochloride, nimetazepam, flurazepam,haloxazolam, flunitrazepam, rilmazafone hydrochloride, lormetazepam,triazolam, etc.], (ii) thienodiazepine sleep inducing drugs[specifically, brotizolam etc.], (iii) non-benzodiazepine sleep inducingdrugs [specifically, zolpidem etc.], (iv) melatonin receptor agonists[specifically, ramelteon etc.]), (v) cyclopyrrolone sleep inducing drugs[specifically, zopiclone etc.], (29) β amyloid vaccines, (30) β amyloiddecomposing enzymes, etc., (31) cerebral function activators[specifically, aniracetam, nicergoline, etc.], (32) cannabinoidmodulators, (33) choline esterase inhibitors [specifically, donepezilhydrochloride, rivastigmine, galantamine hydrobromide, etc.], (34) MAO-Binhibitors [specifically, rasagiline etc.] (35) Parkinson'sdisease-treating agents ((i) dopamine receptor agonists [specifically,levodopa, amantadine hydrochloride, bromocriptine mesilate, pergolidemesilate, cabergoline, talipexole hydrochloride, pramipexolehydrochloride hydrate, selegiline hydrochloride, ropinirolehydrochloride, etc.], (ii) monoamine oxidase inhibitors [specifically,deprenyl, selegiline, remacemide, riluzole, etc.], (iii) anticholinergicdrugs [specifically, trihexyphenidyl, profenamine, biperiden,piroheptine hydrochloride, methixene hydrochloride, mazaticolhydrochloride, etc.], (iv) COMT inhibitors [specifically, entacaponeetc.], (v) therapeutic agents for amyotrophic lateral sclerosis[specifically, riluzole, neurotrophic factors, etc.], (vi) apoptosisinhibitors [specifically, CPI-1189, IDN-6556, CEP-1347, etc.], and (vii)nerve differentiation/regeneration promoters [specifically, leteprinim,xaliproden; SR-57746-A, SB-216763, etc.]).

On the other hand, examples of the above described agent (B) include(36) therapeutic agents for diabetes ((i) PPARγ stimulants (agonists andinhibitors) [specifically, pioglitazone, rosiglitazone, troglitazone,ciglitazone, darglitazone, englitazone, netoglitazone, etc.], (ii)insulin secretion promoters [(a) sulfonylurea agents (specifically,tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide,glipizide, glimepiride, glipentide, gliquidone, glisolamide, tolazamide,etc.), (b) non-sulfonylurea agents etc.], (iii) rapid-acting insulinsecretion promoters (specifically, nateglinide, mitiglinide,repaglinide, etc.), (iv) α-glucosidase inhibitors [specifically,acarbose, voglibose, miglitol, camiglibose, adiposin, emiglitate,pradimicin-Q, salbostatin, etc.], (v) insulin resistance-improvingagents [specifically, (a) PPARγ stimulants, (b) PTP-1B inhibitors, (c)DPP-4 inhibitors [specifically, sitagliptin, vildagliptin, alogliptin,saxagliptin, NVP-DPP-728, etc.], (d) GLP-1 and GLP-1 agonists[specifically, exenatide, liraglutide, etc.], (e) 11β-HSD inhibitors andthe like, (f) GPR40 agonists, (g) GPR119 agonists, and (h) GPR120agonists], (vi) hepatic gluconeogenesis suppressants [specifically,glucagon antagonists etc.], (vii) biguanide agents [specifically,metformin, buformin, phenformin, etc.], (viii) insulin or insulinderivatives [specifically, insulin zinc suspension, insulin lispro,insulin aspart, regular insulin, NPH insulin, insulin glargine, insulindetemir, mix-type insulin, etc.], (ix) α2 antagonists [specifically,midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, etc.]), (37)antiobestic drugs ((i) adrenalin γ3 receptor agonists [specifically,KRP-204, TRK-380/TAC-301, etc.], (ii) CB-1 receptor antagonists[specifically, rimonabant, SR-147778, BAY-65-2520, etc.], (iii)neuropeptide Y (NPY) receptor antagonists [specifically, S-2367 etc.],(iv) anti-feeding drugs [monoamine reuptake inhibitors [specifically,sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically,orilstat, cetilistat, etc.], and (vi) peptide YY (PYY) receptorantagonists, etc.), (38) hyperlipidemia-treating agents such ascholesterol-reducing agents ((i) ω3 fatty acids [specifically, ethylicosapentate (EPA-E preparations, for example, product name: Epadel(registered trademark)), docosahexaenoic acid (DHA), a mixed preparationof ethyl icosapentate and ethyl docosahexaenoate (e.g. product name:LOVAZA™ and Omacor (registered trademark)), etc.], (ii) HMG-CoAreductase inhibitors [specifically, atorvastatin, simvastatin,pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, rosuvastatin, etc.] (iii) HMG-CoA synthetase inhibitors,(iv) cholesterol absorption inhibitors [specifically, ezetimibe], (v)acyl-CoA cholesterol acyl transferase (ACAT) inhibitors, (vi) CETPinhibitors, (vii) squalene synthetase inhibitors, (viii) antioxidants[specifically, probucol etc.], (ix) PPARα agonists [specifically,clofibrate, etofibrate, fenofibrate, bezafibrate, ciprofibrate,gemfibrozil, KRP-101, etc.], (x) PPARδ agonists, (xi) LXR agonists,(xii) FXR agonists [specifically, INT-747 etc.], (xiii) MTTP inhibitors,(xiv) squalene epoxidase inhibitors, etc.), (39) antihypertensive agents((i) diuretics [specifically, trichlormethiazide, hydrochlorothiazide,mefruside, indapamide, meticrane, chlorthalidone, tripamide, furosemide,torasemide, bumetanide, ethacrynic acid, spironolactone, triamteren,eplerenone, etc.], (ii) calcium receptor antagonists [specifically,amlodipine, felodipine, nicardipine, nifedipine, nimodipine,nitrendipine, nilvadipine, aranidipine, azelnidipine, manidipine,barnidipine, efonidipine, cilnidipine, benidipine, diltiazem, etc.],(iii) angiotensin converting enzyme inhibitors (ACEI) [specifically,captopril, lisinopril, enalapril, delapril, perindopril, benazepril,trandolapril, quinapril, alacepril, imidapril, temocapril, cilazapril,etc.], (iv) angiotensin receptor blockers (ARB) [specifically, losartan,olmesartan, telmisartan, valsartan, candesartan cilexetil, irbesartan,etc.], (v) direct renin inhibitors [specifically, aliskiren etc.], (vi)a receptor blockers [specifically, tolazoline, phentolamine, doxazosin,prazosin, bunazosin, terazosin, urapidil, etc.], (vii) β receptorblockers [specifically, bopindolol, pindolol, timolol,dichloroisoprenaline, alprenolol, carteolol, indenolol, bunitrolol,penbutolol, propranolol, nadolol, nipradilol, tilisolol, acebutolol,celiprolol, metoprolol, atenolol, bisoprolol, betaxolol, practolol,bevantolol, butoxamine, carvedilol, amosulalol, arotinolol, labetalol,etc.], (viii) α₁β blockers [specifically, carvedilol, labetalol,arotinolol, bevantolol, etc.], and (ix) α₂ receptor stimulants[specifically, clonidine, methyldopa, guanfacine, etc.]), (40)non-steroidal anti-inflammatory agents [specifically, meloxicam,teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin,indomethacin, etc.], (41) disease-modifying antirheumatic drugs(DMARDs), (42) anti-cytokine agents [specifically, TNF inhibitors andMAP kinase inhibitors], (43) steroid drugs [specifically, dexamethasone,hexestrol, cortisone acetate, etc.], (44) sex hormones or derivativesthereof [specifically, progesterone, estradiol, estradiol benzoate,etc.], and (45) parathyroid hormone (PTH).

By using the drug of the present invention in combination with theexisting drugs on the above described diseases, it is possible to reducethe doses of the existing drugs, and it is also possible to reduce theadverse drug reactions of the existing drugs. Naturally, application ofthe combined-use method using the present drug is not limited to theabove described diseases, and the combined drugs are not limited to theabove exemplified compounds.

The administration form of the compound in the present invention and thecombined drug is not particularly limited. It is appropriate if thecompound in the present invention may be combined with the combined drugupon administration. Examples of such an administration form include:

(1) administration of a single preparation obtained by simultaneousformulation of the compound in the present invention and the combineddrug,(2) simultaneous administration of two types of preparations obtained byseparately formulating the compound in the present invention and thecombined drug via a single administration route,(3) time-lag administration of two types of preparations obtained byseparately formulating the compound in the present invention and thecombined drug via a single administration route,(4) simultaneous administration of two types of preparations obtained byseparately formulating the compound in the present invention and thecombined drug via different administration routes, and(5) time-lag administration of two types of preparations obtained byseparately formulating the compound in the present invention and thecombined drug via different administration routes (for example,administration in the order of the compound in the present invention andthe combined drug, or in an opposite order).

Hereinafter, these administration forms are collectively abbreviated asthe “combination agent of the present invention.”

Upon administration of the combination agent of the present invention,the combined drug and the compound in the present invention may beadministered at the same time. Otherwise, after administration of thecombined drug, the compound in the present invention may beadministered, or after administration of the compound in the presentinvention, the combined drug may be administered. In the case oftime-lag administration, such a time lag is different depending on anactive ingredient to be administered, dosage form, and administrationmethod. For example, when the combined drug is administered in advance,there is applied a method which comprises administering the compound inthe present invention within 1 minute to 3 days, preferably within 10minutes to 1 day, and more preferably within 15 minutes to 1 hour, afteradministration of the combined drug. When the compound in the presentinvention is administered in advance, there is applied a method whichcomprises administering the combined drug within 1 minute to 1 day,preferably within 10 minutes to 6 hours, and more preferably within 15minutes to 1 hour, after administration of the compound in the presentinvention.

The amount of the combined drug is not particularly limited, as long asit does not cause a problem regarding adverse drug reactions. The dailydose of the combined drug is different depending on administrationtarget, administration route, target disease, symptoms, etc. Forexample, when such a combined drug is administered to a schizophreniapatient (adult; body weight: approximately 60 kg) via oraladministration, it is administered at a single dose of generallyapproximately 0.1 to approximately 20 mg/kg body weight, preferablyapproximately 0.2 to 10 mg/kg body weight, and more preferablyapproximately 0.5 to approximately 10 mg/kg body weight. It is desirableto administer this dose once or divided over several administrations(e.g. three times) per day.

When the compound in the present invention is used in combination with acombined drug, the amounts of both agents can be reduced within a saferange, while taking into consideration the opposite effects of theagents.

The combination agent of the present invention has low toxicity, and forexample, the compound in the present invention, or (and) the abovedescribed combined drug can be mixed with a pharmacologically acceptablecarrier according to a known method, so as to prepare a pharmaceuticalcomposition, for example, a tablet (including a sugar-coated tablet anda film-coated tablet), a powder agent, a granule, a capsule (including asoft capsule), a liquid agent, an injection, a suppository, asustained-release agent, etc. These agents can be safely administeredvia oral or parenteral administration.

As a pharmacologically acceptable carrier that may be used in theproduction of the combination agent of the present invention, the samecarriers as those used in the above described pharmaceutical compositionof the present invention can be used.

The mixing ratio between the compound in the present invention and thecombined drug in the combination agent of the present invention can beselected, as appropriate, depending on administration target,administration route, disease, etc. It may also be possible to use theabove described combined drug by mixing two or more types of combineddrugs at an appropriate ratio.

The dose of the combined drug can be selected, as appropriate,considering a clinically used dose as a standard. In addition, themixing ratio between the compound in the present invention and thecombined drug can be selected, as appropriate, depending onadministration target, administration route, target disease, symptoms,combination, etc. For instance, when the administration target is ahuman, the combined drug may be used at a ratio of 0.01 to 100 parts byweight, based on 1 part by weight of the compound in the presentinvention. For instance, the content of the compound in the presentinvention in the combination agent of the present invention is differentdepending on the form of a preparation. The compound in the presentinvention is used at a weight percentage of generally approximately0.01% to 99.9%, preferably approximately 0.1% to 50%, and morepreferably approximately 0.5% to 20%, based on the total weight of thepreparation.

The content of the combined drug in the combination agent of the presentinvention is different depending on the form of a preparation. Thecombined drug is used at a weight percentage of generally approximately0.01% to 99.9%, preferably approximately 0.1% to 50%, and morepreferably approximately 0.5% to 20%, based on the total weight of thepreparation.

The content of an additive such as a carrier in the combination agent ofthe present invention is different depending on the form of apreparation. The additive is used at a weight percentage of generallyapproximately 1% to 99.99%, and preferably approximately 10% to 90%,based on the total weight of the preparation.

Even when the compound in the present invention and the combined drugare formulated separately, the same contents as those described abovemay be applied.

Since the dose is fluctuated depending on various conditions, asdescribed above, there is a case in which a dose lower than theaforementioned dose is sufficient. On the other hand, there is also acase in which a dose higher than the aforementioned dose range needs tobe administered.

The compound in the present invention can be administered alone or in acombination with a pharmaceutically acceptable carrier, once or dividedover multiple administrations. Examples of a suitable pharmaceuticalcarrier include an inactive solid diluent or filler, a sterilizedaqueous solution, and various organic solvents. Then, a pharmaceuticalcomposition formed from these substances can be easily administered invarious administration forms such as a tablet, a powder agent, alozenge, a liquid preparation, syrup, or injection. Such apharmaceutical composition may comprise additional components such as aflavor, a binder, and an excipient, depending on the situation.Accordingly, the compound in the present invention can be formulatedinto a form suitable for oral, buccal, nasal, parenteral (e.g.intravenous, intramuscular, or subcutaneous), transdermal (e.g. patch)or rectal administration, or inhalation or insufflation administration.

[Formulation of Preventive and/or Therapeutic Agents of the PresentInvention]

The pharmaceutical agent of the present invention is administered in theform of a pharmaceutical composition.

The pharmaceutical composition of the present invention may comprise atleast one compound represented by the formula (I) of the presentinvention, and it is prepared by combining the compound in the presentinvention with pharmaceutically acceptable additives. More specifically,various dosage forms can be prepared by appropriately combining thecompound in the present invention with excipients (e.g. lactose,sucrose, mannit, crystalline cellulose, silicic acid, corn starch, andpotato starch), binders (e.g. celluloses (hydroxypropyl cellulose (HPC)and hydroxypropylmethyl cellulose (HPMC)), and crystalline cellulose,sugars (lactose, mannit, sucrose, sorbitol, erythritol, and xylitol),starches (corn starch and potato starch), pregelatinized starch,dextrin, polyvinyl pyrrolidone (PVP), macrogol, and polyvinyl alcohol(PVA)), lubricants (e.g. magnesium stearate, calcium stearate, talc, andcarboxymethyl cellulose), disintegrators (e.g. starches (corn starch andpotato starch), carboxymethyl starch sodium, carmellose, carmellosecalcium, croscarmellose sodium, and crospovidone), coating agents (e.g.celluloses (hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose(HPMC), aminoalkyl methacrylate copolymer E, and methacrylic acidcopolymer-LD), plasticizers (e.g. triethyl citrate and macrogol),masking agents (e.g. titanium oxide), coloring agents, flavoring agents,antiseptics (e.g. benzalkonium chloride and p-oxybenzoic acid ester),isotonizing agents (e.g. glycerin, sodium chloride, calcium chloride,mannitol, and glucose), pH adjusters (e.g. sodium hydroxide, potassiumhydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, andbuffers such as a phosphate buffer), stabilizers (e.g. sugar, sugaralcohol, and xanthan gum), dispersants, antioxidants (e.g. ascorbicacid, butylhydroxyanisole (BHA), propyl gallate, and dl-α-tocopherol),buffering agents, preservatives (e.g. paraben, benzyl alcohol, andbenzalkonium chloride), aromatics (e.g. vaniline, l-menthol, and roseoil), solubilizers (e.g. polyoxyethylene hydrogenated castor oil,polysorbate 80, polyethylene glycol, phospholipid cholesterol, andtriethanolamine), absorption promoters (e.g. sodium glycolate, sodiumedetate, sodium caprylate, acylcarnitines, and limonene), gelatinizers,suspending agents, emulsifiers, or commonly used suitable additives orsolvents.

Various dosage forms include a tablet, a capsule, a granule, a powderagent, a pill, an aerosol, an inhalant, an ointment, a patch, asuppository, an injection, a troche, a liquid preparation, a spirit, asuspension, an extract, and an elixir. In addition, the pharmaceuticalcomposition of the present invention can be administered to a patient,via oral administration, subcutaneous administration, intramuscularadministration, intranasal administration, transdermal administration,intravenous administration, intraarterial administration, perineuraladministration, epidural administration, intrathecal administration,intraventricular administration, intrarectal administration, inhalation,etc.

The compound in the present invention can be formulated into aninjection administered via parenteral administration, which includes theuse of a common catheter technique or infusion. To such an injectionpreparation, a preservative is added, and it can be provided in a unitadministration form, for example, in an ampule or in a multiple-dosecontainer. Such a preparation can take a form such as a suspension agentin an oily or aqueous vehicle, a liquid agent, or an emulsion, and itmay comprise agents for drug formulation, such as a suspending agent, astabilizer, and/or a dispersant. Otherwise, an active ingredient can bein a powdery form, which can be reconstituted with a suitable vehicle,such as a sterilized pyrogen-removed water, before use.

When a product solution is necessary, such a product solution can beproduced by dissolving an isolated inclusion complex in water (oranother aqueous medium) that is in an amount sufficient for generationof a solution with strength necessary for oral or parenteraladministration to a patient. Such a compound can be formulated into afast dissolving dosage form (fddf), which is designed such that anactive ingredient thereof is released in an oral cavity. Such apreparation is formulated using a matrix comprising fast dissolvinggelatin as a base in many cases. Such a dosage form is well known, andit can be used to deliver a wide range of drugs. Almost all of such fastdissolving dosage forms utilize gelatin as a carrier or astructure-forming agent. Typically, gelatin is used to impart to adosage form, sufficient strength for preventing the preparation frombeing broken when it is removed from a package. Once such gelatin is putinto the mouth, the dosage form thereof can be immediately decomposed.Otherwise, in order to obtain the same effects as described above,various types of starches can be used.

The compound in the present invention can also be formulated into arectal composition such as a suppository or retention enema, wherein therectal composition comprises, for example, a common suppository basesuch as cacao butter or other glycerides.

In the case of administration via intranasal administration orinhalation, the compound in the present invention is convenientlydelivered in the form of a solution or a suspension from a pump spraycontainer that is compressed by a patient or is delivered by a pump, orin the form of an aerosol spray presentation delivered from apressurized container or a nebulizer using a suitable spraying agentsuch as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or another suitable gas. Inthe case of pressurized aerosol, the dosage unit can be determined byproviding a valve for delivering the measured amount. A pressurizedcontainer or a nebulizer may comprise a solution or a suspension of anactive compound. A capsule agent and a cartridge agent (for example,produced from gelatin), which are used with an inhalator or a filler,can be formulated from a mixed powder of the compound in the presentinvention and a suitable powder base such as lactose or starch.

With regard to an aerosol preparation for treating the aforementionedcondition in an average adult, the measured dose or “one puff” ofaerosol is determined such that it comprises preferably approximately 20mg to approximately 1000 mg of the compound in the present invention.The total daily dose of aerosol is determined in the range fromapproximately 100 mg to approximately 10 mg. The aerosol preparation isadministered several times, for example, 2, 3, 4 or 8 times per day, forexample at 1, 2 or 3 doses every administration.

The content of the compound in the present invention in thepharmaceutical composition of the present invention is differentdepending on dosage form, the dose of the compound in the presentinvention, etc. For example, the compound in the present invention isused at a weight percentage of approximately 0.01% to 100%, andpreferably 0.1% to 95%, based on the total weight of the composition.

In order to treat the aforementioned condition, the dose of the compoundin the present invention is different depending on administrationtarget, administration route (oral, parenteral, rectal, buccal, etc.),target disease, symptoms, and the like. For example, in the case of oraladministration to a schizophrenia patient (adult; body weight:approximately 60 kg), the compound in the present invention isadministered at a dose of generally approximately 0.1 to approximately20 mg/kg body weight, preferably approximately 0.2 to 10 mg/kg bodyweight, and more preferably approximately 0.5 to approximately 10 mg/kgbody weight, per administration. This dose is desirably administeredonce or divided over several administrations (for example, three times)per day.

Pharmacological Experimental Examples

The present invention will be specifically described in the followingexperimental examples. However, these experimental examples are notintended to limit the present invention.

The following Pharmacological Experimental Examples 1 to 7 providemethods for examining the effectiveness of the compound in the presentinvention.

Pharmacological Experimental Example 1 In Vitro Evaluation of Compounds

(Evaluation of Enzyme Inhibitory Activity: Human PDE10 InhibitoryEffect)

IMAP TR-FRET Phosphodiersterase Evaluation Assay Kit (Molecular Device)was used for the measurement. Ten μL of a diluted test compound havingeach concentration and 5 μL of the enzyme PDE10 (BPA Bioscience) thathad been diluted to 2 ng/mL with 1×IMAP Reaction Buffer (prepared with5× included with the kit, 10 mM Tris-HCl, pH=7.2, 10 mM MgCl₂, 0.05%NaN₃, and 0.1% BSA) containing 0.1% BSA were added to a 384-well plate(Corning). The obtained mixture was then pre-incubated at roomtemperature for 5 minutes. Thereafter, 5 μL of cAMP substrate solutionwhich was included with the kit and diluted to 400 nM with 1×IMAPReaction Buffer containing 0.1% BSA, was added to the reaction solution,and the obtained mixture was reacted at room temperature for 60 minutes.Thereafter, 60 μL of an IMAP TR-FRET Binding solution included with thekit was further added to the reaction solution, and the obtained mixturewas then left for 3 hours or more. Subsequently, using ARVO SX(PerkinElmer), the fluorescent intensity of Terbium (Emission=490 nm)and TR-FRET (Emission=520 nm) in the reaction solution were measured atan excitation wavelength of 340 nm, so as to calculate the amount of thegenerated 5′-AMP. The count of a well to which a solvent had been addedinstead of the test compound was set at 0%, and the count of a well towhich the enzyme PDE10 had not been added was set at 100%. Thus, theinhibitory activity of each test compound was calculated.

The PDE10 inhibitory activity of the test compound was indicated with anIC₅₀ value. The compound in the present invention having an IC₅₀ valueof 5 to 100 nmol/L was indicated with +, and the compound in the presentinvention having an IC₅₀ value of less than 5 nmol/L was indicated with++. The test compounds are shown in Table 3 (Table 3-1 and Table 3-2).

TABLE 3-1 Example IC₅₀ value 1.1 ++ 1.2 ++ 1.3 ++ 1.4 ++ 1.5 ++ 1.6 ++1.7 ++ 2.1 ++ 2.2 ++ 2.3 ++ 2.4 ++ 2.5 ++ 2.6 ++ 2.7 ++ 2.8 ++ 2.9 ++2.10 ++ 2.11 ++ 2.12 ++ 2.13 ++ 2.14 ++ 2.15 ++ 2.16 + 2.17 + 2.18 +2.19 ++ 2.20 ++ 2.21 + 2.22 ++ 2.23 + 2.24 + 2.25 + 2.26 + 2.27 + 2.28++ 2.29 ++ 3.1 ++ 3.2 ++ 3.3 ++ 3.4 ++ 3.5 ++ 3.6 ++ 3.7 ++ 3.8 ++ 3.9++ 3.10 ++ 3.11 ++ 3.12 ++ 3.13 ++ 3.14 ++ 3.15 ++ 3.16 ++ 3.17 ++ 3.18++ 3.19 ++ 3.20 ++ 3.21 + 3.22 ++ 3.23 ++ 3.24 ++ 3.25 ++ 3.26 ++ 3.27++ 3.28 ++ 3.29 ++ 3.30 ++ 3.31 ++ 3.32 ++ 3.33 ++ 3.34 ++ 3.35 ++ 3.36++ 3.37 ++ 3.38 ++ 3.39 ++ 3.40 ++ 3.41 ++ 3.42 ++ 3.43 ++ 3.44 ++ 3.45++ 3.46 ++ 3.47 ++ 3.48 ++ 3.49 ++ 3.50 ++ 3.51 ++ 3.52 ++ 3.53 ++ 3.54++ 4.1 ++ 4.2 ++

TABLE 3-2 Example IC₅₀ 4.3 ++ 4.4 ++ 4.5 ++ 4.6 ++ 4.7 ++ 4.8 ++ 4.9 ++4.10 ++ 4.11 ++ 4.12 ++ 4.13 ++ 3.14 ++ 4.15 ++ 4.16 ++ 4.17 ++ 4.18 ++4.19 ++ 4.20 ++ 4.21 ++ 4.22 ++ 4.23 ++ 4.24 ++ 4.25 ++ 4.26 ++ 4.27 ++4.28 ++ 4.29 ++ 4.30 ++ 4.31 ++ 4.32 ++ 4.33 ++ 4.34 ++ 4.35 ++ 4.36 +5.1 ++ 5.2 + 5.3 ++ 5.4 ++ 5.5 ++ 5.6 ++ 5.7 ++ 5.8 + 5.9 + 5.10 +5.11 + 5.12 + 5.13 + 5.14 + 5.15 + 5.16 + 5.17 ++ 5.18 + 5.19 + 5.20 +5.21 + 5.22 + 5.23 + 5.24 + 5.25 + 5.26 + 5.27 + 5.28 + 5.29 ++ 5.30 +5.31 + 5.32 + 5.33 + 5.34 ++ 5.35 + 5.36 ++ 5.37 + 5.38 + 5.39 + 5.40 +5.41 + 5.42 + 5.43 + 5.44 + 5.45 ++ 5.46 ++ 5.47 +

The effectiveness of the compound in the present invention as atherapeutic agent for mental disorder and neurodegenerative disorderwill be demonstrated by the following Pharmacological ExperimentalExample 2 (an experiment regarding suppression of locomotor activity byoral administration of a test compound to rats 30 minutes beforeadministration of MK-801).

Pharmacological Experimental Example 2 Evaluation of MK-801-InducedLocomotor Activity (Animals)

Male Sprague-Dawley rats were purchased. After the animals had arrivedat a rearing facility, they were subjected to habituation for at leastone week and were then used in the experiment. The animals were rearedin a laboratory in which temperature and humidity were controlled, undera light-dark cycle of 12:12 hours. The animals were freely fed with dietand water.

(Administration of Drug)

The test compound was suspended in a 0.5 w/v % Methyl Cellulose 400Solution (Wako Pure Chemical Industries, Ltd., Japan), and it was thenadministered to the rats via oral administration (p.o.). (+)-MK-801hydrogen maleate((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminehydrogen maleate, Sigma-Aldrich, St. Louis, Mo.) was dissolved in aphysiological saline, and it was then administered to the rats viasubcutaneous administration (s.c.). To the rats, the test compound wasadministered at a volume of 5 mL/kg body weight, and MK-801 wasadministered at a volume of 1 mL/kg body weight.

(Antagonism on the Increase of Locomotor Activity Induced by MK-801)

Evaluation of the increase of locomotor activity in rodents caused bypsychostimulants (e.g., amphetamine, cocaine, methanephetamine, MK-801,and phencyclidine) has been widely used as an animal models forschizophrenia (Schizophrenia Bulletin 2010, vol. 36: 1066-1072;Psychopharmacology 1999, vol. 145: 237-250). The antagonism of a testcompound on the increase of locomotor activity in rats, which had beeninduced by MK-801, was examined Before the test, male Sprague-Dawleyrats (approximately 300 g) were habituated for 60 minutes or more in abreeding cage in a room, in which the measurement was to be carried out.After the habituation, either a solvent or a compound (0.3 or 1 mg/kgbody weight) was administered to the animals via oral administration,and thereafter, the animals were immediately returned into the breedingcage. Sixty minutes after administration of the test compound, theanimals were removed from the breeding cage again, and a solvent (aphysiological saline) or MK-801 (0.2 mg/kg body weight) was administeredto the animals via subcutaneous administration. Immediately after theadministration, the animals were placed in a locomotor activitymeasurement chamber equipped with an infrared sensor (Muromachi KikaiCo., Ltd., Japan), and the measurement was then started. Locomotoractivity was counted every 10 minutes. The cumulative count for 120minutes after administration of MK-801 was calculated for each treatmentgroup. All data are shown as a mean value and a standard error of themean value. Statistical analysis was carried out, by applying aStudent's t-test for a comparison between a control group and a singleMK-801 administration group (there was a significant difference whenp<0.05), and by applying a Dunnett's test for a comparison between asingle MK-801 administration group and a test compound administrationgroup (there was a significant difference when p<0.05).

Pharmacological Experimental Example 3 Solubility Test (1) DMSOPrecipitation Solubility (Kinetic Solubility)

A DMSO solution of the compound in the present invention (10 mM) wasadded to a 50 mM phosphate buffer (pH 7.4) to a final concentration of100 μM. The obtained solution was incubated at room temperature for 1.5hours, while being stirred at 600 rpm, and the resulting solution wasthen filtered through a filter plate (4 μm, MultiScreen SolubilityFilter Plate (Millipore)). Thereafter, using a plate reader (PowerscanHT (Dainippon Pharma Co., Ltd.)), the absorbance of the filtrate wasmeasured at a maximum absorption wavelength. At the same time, DMSOsolutions, to which test compounds each having a known concentration (1,3, 10, 30, and 100 μM) had been added, were used as calibration curvestandard solutions, and the absorbance of each standard solution wasthen measured, so as to prepare a calibration curve. Based on theabsorbance values of the filtrate and the standard solution, thesolubility (μM) of the compound was calculated.

(2) Crystal Solubility (Thermodynamic Solubility)

The compound in the present invention was added to water to aconcentration of 1 mg/mL. The obtained solution was left at rest at 37°C. for 24 hours, and was then centrifuged. The obtained supernatant wasanalyzed by HPLC, a peak was then detected at a maximum absorptionwavelength, and a peak area was then measured. Likewise, using DMSOsolutions, to which test compounds each having a known concentration(0.03, 0.1, 0.3, 1, 3, and 10 μg/mL) had been added as calibration curvestandard solutions, each peak area was measured, and the solubility(μg/mL) of the compound was calculated based on the peak area of thecalibration curve.

Pharmacological Experimental Example 4 Metabolic Stability Test

A DMSO solution of the compound in the present invention (10 mM) wasadded to a hepatic microsome solution (human, mouse; XenoTech) and anNADPH generation solution (water containing β-NADP, Glucose-6-Phosphate,G-6-PDH (Y), and MgCl₂) to a final concentration of 1 μM. This solutionwas incubated at 37° C. for 20 minutes, and the reaction was thenterminated with adding acetonitrile. The reaction solution was subjectedto centrifugal filtration using a filter plate (MultiScreenHTS-HV Plate(Millipore)), and the test compound in the filtrate was then measuredusing high performance liquid chromatography/mass spectrometry.Likewise, a sample with a reaction time of 0 minute was measured as acontrol, and a decomposition rate (%) was then calculated based on theratio of the microsome reaction sample and the control.

Pharmacological Experimental Example 5 hERG Inhibition Test According toPatch-Clamp Method

The effect of the test compound on an hERG (human ether-a-go-go relatedgene) channel was measured using a fully-automated patch-clamp system(Patchliner (Nanion)). In order to confirm the hERG I_(Kr) current ofcells (hERG-HEK (Upstate)), a membrane potential was kept at −80 mV, anddepolarization pulse was periodically added thereto. After the generatedcurrent had been stabilized, a test compound was added. The effect ofthe test compound on the hERG channel was confirmed based on a change ina tail current induced by repolarization pulse performed at −40 mV for0.5 seconds, after the depolarization pulse at 40 mV for 0.5 seconds.Stimulation was given at a frequency of once every 10 seconds. Themeasurement was carried out at room temperature. The hERG channelinhibitory rate was calculated as a reduction rate (suppression rate) ofthe tail current two minutes after application of the test compound,comparison with the maximum tail current before application of the testcompound.

Calculation of such a suppression rate shows the possibility of inducingQT extension caused by the drug and the subsequent fatal adverse drugreactions (ventricular tachycardia, sudden death, etc.).

Pharmacological Experimental Example 6 Pharmacokinetics Test (MouseCassette PK)

The the compound in the present invention was administered to 7- or8-week-old male C57BL/6J Jcl mice at a single oral dose of 1 mg/kg(administered solvent: DMSO:Tween 80:ultrapure water=1:1:8; 10 mL/kg).Thereafter, 0.25, 0.5, 1, or 2 hours later, blood was collected from theabdominal portion of vena cava of each mouse. The collected blood wascentrifuged (3000 rpm, 15 minutes, and 4° C.), and using the obtainedplasma, the test compound in the plasma was measured by high performanceliquid chromatography/mass spectrometry. Likewise, standard solutions,to which test compounds each having a known concentration (0.01, 0.02,0.05, 0.1, 0.2, 0.5, and 1 μg/mL) had been added, were measured, and acalibration curve was prepared. The plasma concentrations (μg/mL) werecalculated from the prepared calibration curve, and the highest plasmaconcentration was defined as Cmax (μg/mL).

Pharmacological Experimental Example 7 Protein Binding Test

A DMSO solution of the compound in the present invention (10 mM) wasadded to normal plasma (human and rat) to a final concentration of 10μM. Dialysis was carried out at 37° C. for 4 hours in a simpleequilibrium dialyzer (RED Device (Linden Bioscience)). Thereafter, theinner solution (plasma side) and the outer solution (PBS side) of adialysis membrane were subjected to high performance liquidchromatography/mass spectrometry, so that the test compound in thesample was measured. A non-binding percentage (%) was calculated basedon the ratio between the PBS side and the plasma side, and a proteinbinding percentage (%) was then calculated from 100-non-bindingpercentage (%).

Pharmacological Experimental Example 8 Safety Test

The compound in the present invention was administered to mice or ratsin a single dose via oral administration. No animal died, andsignificant behavior abnormality was not observed. Thus, the safety ofthe compound in the present invention was demonstrated.

The above results demonstrated that the compound in the presentinvention has an excellent PDE10 inhibitory effect. In addition, noabnormality was observed in the safety study, and thus, it was alsodemonstrated that the compound in the present invention has lowtoxicity.

Moreover, as a result of the above described tests, the compound in thepresent invention was confirmed to be favorable in terms of one ofsolubility, metabolic stability, pharmacokinetics, the avoidance of hERGchannel inhibitory effect, etc.

Therefore, it is anticipated that the compound in the present inventionwill be used as a selective PDE10 inhibitor in agents for preventingand/or treating diseases such as certain types of mental disorders andconditions, such as mental disorder, paranoid disorder, and drug-inducedpsychosis, anxiety disorders such as panic disorder andobsessive-compulsive disorder, motor disorders including Parkinson'sdisease and Huntington's disease, mood disorder, neurodegenerativedisorder, disorder involving deficits in attention and/or cognition,obesity, and drug addiction.

The compound in the present invention is anticipated to exhibitpromising preventive or therapeutic effects on various types ofdiseases, as described below. Specifically, the present compound isanticipated to exhibit promising therapeutic effects on (1) paranoid,disorganized, catatonic, undifferentiated, or residual schizophrenia,(2) schizophreniform disorder, (3) paranoid or depressiveschizoaffective disorder, (4) paranoid disorder, (5) substance-inducedmental disorder, (6) psychosis induced by alcohol, amphetamine,cannabis, cocaine, a hallucinatory drug, an inhalant, opioid, orphencyclidine, (7) paranoic personality disorder, (8) schizotypalpersonality disorder, (9) Huntington's disease, (10) dyskinesiaassociated with dopamine agonist therapy, (11) Parkinson's disease, (12)restless legs syndrome, (13) essential tremor, (14) obsessive-compulsivedisorder, (15) Tourette's syndrome, (16) tic disorder, (17) panicdisorder, (18) agoraphobia, (19) specific phobias, (20) social phobias,(21) posttraumatic stress disorder, (22) acute stress disorder, (23)generalized anxiety disorder, (24) dementia; Alzheimer's disease,multiple cerebral infarction, alcoholic dementia or other drug-relateddementia, dementia associated with intracranial tumor or brain damage,dementia associated with Huntington's disease or Parkinson's disease,AIDS-related dementia, or frontotemporal dementia, (25) delirium, (26)amnestic disorder, (27) mental retardation, (28) learning disorder;dyslexia, mathematics disorder, or disorder of written expression, (29)attention-deficit hyperactivity disorder, (30) age-related cognitivedecline, (31) major depressive episode (mild level, moderate level, orsevere level type), manic episode, mixed affective episode, or hypomanicepisode, (32) atypical depression, (33) melancholic depression, (34)catatonic depression, (35) postpartum mood episode, (36) postapoplecticdepression, (37) major depressive disorder, (38) dysthymicdisorder/dysthymia, (39) minor depressive disorder, (40) premenstrualdysphoric disorder, (41) postschizophrenic depressive disorder, (42)major depressive disorder occurring with paranoid disorder or mentaldisorder such as schizophrenia, (43) bipolar disorder; bipolar disordertype I and bipolar disorder type II, (44) cyclothymic disorder, (45)neurodegeneration associated with brain damage, (46) neurodegenerationassociated with stroke or neurodegeneration associated with cerebralinfarction, (47) hypoglycemia-induced neurodegeneration, (48)neurodegeneration associated with epileptic seizure, (49)neurodegeneration associated with neurotoxic addiction, (50) multiplesystem atrophy, (51) neurodegeneration of striatal medium-sized spinyneurons, and the like.

EXAMPLES

Hereinafter, the present invention will be described more in detail inthe following examples. However, these examples are not intended tolimit the present invention.

For the measurement of nuclear magnetic resonance (NMR) spectra, JEOLJNM-ECX 400 (JEOL JNM-ECX 400) FT-NMR (manufactured by JEOL Ltd.) andJEOL JNM-ECX 300 (JEOL JNM-ECX 300) FT-NMR (manufactured by JEOL Ltd.)were used. LC-Mass was measured by any of the following methods. WatersFractionLynx MS System (manufactured by Waters) was used, and SunFireColumn (4.6 mm×5 cm, 5 μm) manufactured by Waters was used as a column.Regarding a mobile phase, the following gradient conditions wereapplied. That is, [Method A] methanol:0.05% acetic acid aqueoussolution=10:90 (0 minute)-100:0 (5 minutes)-100:0 (7 minutes), or[Method B] methanol:0.05% trifluoroacetic acid aqueous solution=10:90 (0minute)-100:0 (5 minutes)-100:0 (7 minutes). UPLC/MS was measured usingWaters UPLC-ZQ MS System (manufactured by Waters), and using MGIII-H(2.1 mm×5 cm, 3 μm) manufactured by Shiseido Co., Ltd., as a column.Regarding a mobile phase, the following gradient conditions wereapplied: [Method C] methanol:0.05% trifluoroacetic acid aqueoussolution=5:95 (0 minute)-100:0 (1 minute)-100:0 (2 minutes). As afractionation system, gradient conditions, which were appropriatelyaltered depending on compounds, were used. As a microwave, MicrowaveReactor (Initiator™) manufactured by Biotage(R) was used.

Example 1.1 Synthesis of1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

A 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.37 g) and potassium acetate (3.5 g) wereadded to a dimethyl sulfoxide (10 ml) solution of4-bromo-1-methyl-1H-pyrazole-5-carboxylate (2.0 g) and5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (4.1 g). The obtainedmixture was stirred in a nitrogen atmosphere at 100° C. for 4 hours.Thereafter, the reaction solution was cooled, and water (50 ml) was thenadded thereto, followed by extraction with ethyl acetate (100 ml) twice.Organic layers were gathered. The gathered organic layer wassuccessively washed with water and a saturated saline, and was thendried over anhydrous sodium sulfate. The solvent was distilled awayunder reduced pressure, and the obtained residue was then purified bysilica gel column chromatography (silica gel: eluent; heptane:ethylacetate=90:10-40:60), so as to obtain the title compound (1.0 g) in theform of a brown liquid.

<Step 2> Synthesis of methyl1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate

An aqueous solution (0.5 ml) of potassium carbonate (246 mg) was addedto a 1,4-dioxane (1 ml) solution of the methyl4-(5,5-dimethyl-1,3,2-dioxaborinan)-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(150 mg) obtained in (Example 1.1) <Step 1>, 2-bromo-5-methylpyridine(102 mg), bis(dibenzylideneacetone)palladium (17 mg), and2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1′-biphenyl (57 mg). Theobtained mixture was stirred in a nitrogen atmosphere at 100° C. for 1hour. Thereafter, the reaction solution was extracted with ethylacetate. The extract was washed with a saturated saline, and was thendried over anhydrous sodium sulfate. The solvent was distilled awayunder reduced pressure, and the obtained residue was then purified bysilica gel column chromatography (silica gel: eluent; heptane:ethylacetate=100:0-40:60), so as to obtain the title compound (110 mg) in theform of a yellow liquid.

<Step 3> Synthesis of1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid

An aqueous solution (1.3 ml) of sodium hydroxide (50 mg) was added to amethanol (1.3 ml) solution of the methyl1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (100 mg)obtained in (Example 1.1) <Step 2>. The obtained mixture was stirred at70° C. for 1 hour. Thereafter, 1 N hydrochloric acid was added to thereaction solution to adjust the pH value to pH 5, and the reactionmixture was then extracted with methylene chloride three times. Theorganic layer was successively washed with water and a saturated saline,and was then dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure, and a mixed solution of diethylether and heptane (1:1) was added to the obtained residue to solidifyit, so as to obtain the title compound (74 mg) in the form of a whitesolid.

<Step 4> Synthesis of1-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Diisopropylethylamine (0.071 ml) was added to an N,N-dimethylformamide(1 ml) solution of 2-phenylimidazo[1,2-a]pyridin-7-amine hydrochloride(25 mg), the 1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid (27 mg) obtained in (Example 1.1) <Step 3>, andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (58 mg). The obtained mixture was stirred at roomtemperature for 14 hours. Thereafter, the reaction solution wasfractionated and purified by LC/MS, so as to obtain the title compound(13 mg) in the form of a white solid.

Example 1.2 Synthesis of1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-4-methylthiazole (106 mg), the title compound (110 mg) wasobtained in a white amorphous form by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate (100 mg)obtained in (Example 1.2) <Step 1>, the title compound (58 mg) wasobtained in the form of a beige solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylicacid (27 mg) obtained in (Example 1.2) <Step 2>, the title compound (6.0mg) was obtained in the form of a light yellow solid by the same methodas that of (Example 1.1) <Step 4> or a method equivalent thereto.

Example 1.3 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4-(difluoromethyl)thiazole (600 mg), the title compound(590 mg) was obtained in a light brown amorphous form by the same methodas that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

An aqueous solution (0.28 ml) of 1 N sodium hydroxide was added to amethanol (1.4 ml) solution of the methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(30 mg) obtained in (Example 1.3) <Step 1>. The obtained mixture wasstirred at 60° C. for 30 minutes. Thereafter, the solvent was distilledaway under reduced pressure, and the obtained residue was then subjectedto azeotropy with toluene (10 ml). Subsequently, diisopropylethylamine(0.15 ml) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (138 mg) were added to an N,N-dimethylformamide (0.72ml) solution of the obtained residue, and the thus obtained mixture wasthen stirred in a nitrogen atmosphere at room temperature for 30minutes. Thereafter, 2-phenylimidazo[1,2-a]pyridin-7-amine (30 mg) wasadded to the reaction solution, and the mixture was then stirred for 18hours 15 minutes. Thereafter, the reaction solution was fractionated andpurified by LC/MS, so as to obtain the title compound (28 mg) in theform of a brown solid.

Example 1.4 Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

N-bromosuccinimide (391 mg) was added to an N,N-dimethylformamide (3.6ml) solution of the methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(200 mg) obtained in (Example 1.3) <Step 1>, and the obtained mixturewas then stirred in a nitrogen atmosphere at 80° C. for 40 minutes.Thereafter, N-bromosuccinimide (391 mg) was further added to thereaction solution, and the obtained mixture was then stirred in anitrogen atmosphere at 80° C. for 15 hours. Thereafter, a sodiumthiosulfate aqueous solution (40 ml) and a saturated sodium hydrogencarbonate aqueous solution (60 ml) were successively added to thereaction solution, and the reaction mixture was then extracted withethyl acetate (60 ml) twice. Organic layers were gathered. The gatheredorganic layer was washed with a saturated saline (100 ml) three times,and was then dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure, and the obtained residue was thendried under reduced pressure, so as to obtain the title compound (274mg) in the form of a brown solid.

<Step 2> Synthesis of methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Toluene (19 ml) and water (1.7 ml) were added to a mixture of the methyl4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(270 mg) obtained in (Example 1.4) <Step 1>, 2,4,6-trimethoxyboroxin(289 mg), palladium acetate (II) (86 mg), tricyclohexylphosphine (251mg), and potassium phosphate (651 mg). The obtained mixture was stirredin a nitrogen atmosphere at 110° C. for 35 minutes. Thereafter, thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (silicagel: eluent; heptane:ethyl acetate=92:8-40:60), so as to obtain thetitle compound (142 mg) in the form of a brown solid.

<Step 3> Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(27 mg) obtained in (Example 1.4) <Step 2>, the title compound (4.3 mg)was obtained in the form of a brown solid by the same method as that of(Example 1.3) <Step 2> or a method equivalent thereto.

Example 1.5 Synthesis of1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-4-(trifluoromethyl)thiazole (291 mg), the title compound(259 mg) was obtained in the form of a light brown solid by the samemethod as that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(33 mg) obtained in (Example 1.5) <Step 1>, the title compound (5.9 mg)was obtained in the form of a white solid by the same method as that of(Example 1.3) <Step 2> or a method equivalent thereto.

Example 1.6 Synthesis of1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-6-(trifluoromethyl)pyridine (269 mg), the title compound(220 mg) was obtained in the form of a colorless liquid by the samemethod as that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylate(33 mg) obtained in (Example 1.6) <Step 1>, the title compound (2.4 mg)was obtained in the form of a brown solid by the same method as that of(Example 1.3) <Step 2> or a method equivalent thereto.

Example 1.7 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(300 mg) obtained in (Example 1.3) <Step 1> and N-chlorosuccinimide (440mg), the title compound (465 mg) was obtained in the form of a brownsolid by the same method as that of (Example 1.4) <Step 1> or a methodequivalent thereto.

<Step 2> Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(460 mg) obtained in (Example 1.7) <Step 1>, the title compound (306 mg)was obtained in the form of a brown solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Diisopropylethylamine (0.30 ml) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(276 mg) were added to an N,N-dimethylformamide (0.72 ml) solution ofthe4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (42 mg) obtained in (Example 1.7) <Step 2>. The obtained mixturewas stirred in a nitrogen atmosphere at room temperature for 30 minutes.Thereafter, 2-phenylimidazo[1,2-a]pyridin-7-amine (30 mg) was added tothe reaction solution, and the obtained mixture was then stirred at 60°C. for 1 hour. Thereafter, the reaction solution was fractionated andpurified by LC/MS to obtain the title compound (1 mg) in the form of alight brown solid.

Example 2.1 Synthesis of1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine hydrochloride

Concentrated hydrochloric acid (0.11 ml) and platinum(IV) dioxide (83mg) were added to a methanol (183 ml) solution of2-phenylimidazo[1,2-a]pyridin-7-amine hydrochloride (900 mg), and theobtained mixture was then stirred in a hydrogen atmosphere for 4 hours.Thereafter, platinum(IV) dioxide (83 mg) was added to the reactionsolution, and the obtained mixture was further stirred in a hydrogenatmosphere for 14 hours 30 minutes. Thereafter, the reaction solutionwas filtered with Celite, and was then washed with methanol (15 ml). Thefiltrate was concentrated under reduced pressure, and diethyl ether (3.6ml) was then added to the obtained residue to solidify it, so as toobtain the title compound (733 mg) in the form of a gray solid.

<Step 2> Synthesis of1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Diisopropylethylamine (70 μl) was added to a N,N-dimethylformamide (1ml) solution of the1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylic acid (22 mg)obtained in (Example 1.2) <Step 2>, the2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine hydrochloride(25 mg) obtained in (Example 2.1) <Step 1>, andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (57 mg). The obtained mixture was stirred at roomtemperature for 2 hours, and then at 60° C. for 1 hour. Thereafter,water (5 ml) was added to the reaction solution, and the reactionmixture was then extracted with ethyl acetate (10 ml). The organic layerwas washed with a saturated saline, and was then dried over anhydroussodium sulfate. The solvent was distilled away under reduced pressure,and the obtained residue was then purified by silica gel columnchromatography (silica gel: eluent; heptane:ethyl acetate=90:10-20:80),so as to obtain the title compound (14 mg) in a white amorphous form.

Example 2.2 Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4,5-dimethylthiazole (274 mg), the title compound (170 mg)was obtained in the form of a white solid by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of sodium4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

An aqueous solution (1 ml) of sodium hydroxide (9.6 mg) was added to amethanol (1 ml) solution of the methyl4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (30 mg)obtained in (Example 2.2) <Step 1>, and the obtained mixture was thenheated to reflux for 15 minutes. Thereafter, the solvent was distilledaway under reduced pressure, and the residue was then subjected toazeotropy with toluene, so as to obtain a crude product of the titlecompound.

<Step 3> Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the sodium4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (31 mg)obtained in (Example 2.2) <Step 2>, the title compound (19 mg) wasobtained in the form of a white solid by the same method as that of(Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.3 Synthesis of1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

A 1 N sodium hydroxide aqueous solution (0.33 ml) was added to amethanol (1.6 ml) solution of the methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(71 mg) obtained in (Example 1.5) <Step 1>, and the obtained mixture wasthen stirred at 60° C. for 30 minutes. Thereafter, the solvent wasdistilled away under reduced pressure, and the obtained residue was thensubjected to azeotropy with toluene (10 ml). Diisopropylethylamine (0.17ml), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (187 mg), and the2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine hydrochloride(35 mg) obtained in (Example 2.1) <Step 1> were added to anN,N-dimethylformamide (0.82 ml) solution of the obtained residue, andthe obtained mixture was then stirred in a nitrogen atmosphere.Thereafter, the reaction solution was fractionated and purified by LC/MSto obtain the title compound (13 mg) in the form of an orange solid.

Example 2.4 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(46 mg) obtained in (Example 1.3) <Step 1>, the title compound (69 mg)was obtained in the form of a light brown solid by the same method asthat of (Example 2.3) or a method equivalent thereto.

Example 2.5 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (50 mg) obtained in (Example 1.7) <Step 2>, the title compound (12mg) was obtained in the form of a brown solid by the same method as thatof (Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.6 Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(32 mg) obtained in (Example 1.4) <Step 2>, the title compound (22 mg)was obtained in the form of a brown solid by the same method as that of(Example 2.3) or a method equivalent thereto.

Example 2.7 Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate

N-bromosuccinimide (9 g) was added to a methylene chloride (200 ml)suspension of methyl5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate hydrochloride (10g) and sodium hydrogen carbonate (16 g) over 5 minutes, while keepingthe temperature at 5° C. or less. The obtained mixture was stirred for10 minutes at the same temperature as described above, andN-bromosuccinimide (9 g) was then added to the reaction solution at atemperature of 5° C. or less. The obtained mixture was stirred at 3° C.for 30 minutes. Thereafter, water (200 ml) was added to the reactionsolution, and the mixture was then stirred. Subsequently, an organiclayer was separated from a water layer, and the water layer was thenextracted with methylene chloride (200 ml) again. Organic layers weregathered. The gathered organic layer was washed with a saturated saline,and the solvent was then distilled away under reduced pressure. Theobtained residue was purified by silica gel column chromatography(silica gel: eluent; heptane:ethyl acetate=60:40-30:70), and theobtained fraction was then concentrated. The obtained residue was washedwith methyl tert-butyl ether, and the filtrate was then concentratedunder reduced pressure, so as to obtain the title compound (14 g) in theform of a yellow solid.

<Step 2> Synthesis of methyl2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate

A tetrahydrofuran (150 ml) solution of the methyl2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate (13g) obtained in (Example 2.7) <Step 1> was cooled to −35° C. Thereafter,isopropylmagnesium bromide (95 ml, 1 M tetrahydrofuran solution) wasadded to the solution over 20 minutes, while keeping the temperature at−30° C. or less, and the reaction solution was then stirred at −35° C.for 30 minutes. Thereafter, water (350 ml) and ethyl acetate (250 ml)were added to the reaction solution, and insoluble matters were thenremoved by filtration with Celite. Subsequently, the filtrate wasseparated into an organic layer and a water layer. The water layer wasextracted with ethyl acetate (250 ml), and the organic layers were thengathered. The gathered organic layer was washed with a saturated saline,and the solvent was then distilled away under reduced pressure. Theobtained residue was purified by silica gel column chromatography(silica gel: eluent; heptane:ethyl acetate=70:30-30:70), so as to obtainthe title compound (6.8 g) in the form of a white solid.

<Step 3> Synthesis of2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid

A 1 N sodium hydroxide aqueous solution (23 ml) was added to a methanol(23 ml) solution of the methyl2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate (6.3 g)obtained in (Example 2.7) <Step 2>, and the obtained mixture was thenstirred at 40° C. for 1 hour. Thereafter, 1 N hydrochloric acid (23 ml)was added to the reaction solution, and the generated solid was thencollected by filtration, followed by washing with water (20 ml). Theobtained solid was subjected to azeotropy with toluene, and was thendried under reduced pressure, so as to obtain the title compound (3.5 g)in the form of a beige solid.

<Step 4> Synthesis of tert-butyl(2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate

Molecular Sieves 4A (6 g) was added to a tert-butanol (45 ml) solutionof the 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylicacid (3.1 g) obtained in (Example 2.7) <Step 3> and triethylamine (9.7ml), and the obtained mixture was then stirred at room temperature for30 minutes. Thereafter, diphenyl phosphate azide (3.8 ml) was added tothe reaction solution, and the obtained mixture was stirred for 30minutes and then at 110° C. for 4 hours. Thereafter, the reactionsolution was filtered with Celite, and insoluble matters were thenwashed with ethyl acetate. After that, ethyl acetate (100 ml) was addedto the filtrate, and the obtained mixture was successively washed with asaturated ammonium chloride aqueous solution (25 ml) three times, asaturated sodium hydrogen carbonate aqueous solution (25 ml) twice, anda saturated saline. Then, the solvent was distilled away under reducedpressure. Methylene chloride was added to the obtained residue, andprecipitated white insoluble matters were then removed by suctionfiltration. The filtrate was concentrated under reduced pressure, andthe obtained residue was then purified by silica gel columnchromatography (silica gel: eluent; heptane:ethyl acetate=60:40-20:80),so as to obtain the title compound (1.3 g) in the form of a white solid.

<Step 5> Synthesis of tert-butyl(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate

A dimethoxyethane (3 ml) and an aqueous solution (1 ml), which containedthe tert-butyl(2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate (150 mg)obtained in (Example 2.7) <Step 4>, (3-fluorophenyl)boronic acid (80mg), tetrakis(triphenylphosphine) palladium (44 mg), and cesiumcarbonate (464 mg), were heated to reflux for 2 hours 30 minutes.Thereafter, the reaction solution was diluted with ethyl acetate (30ml). The thus diluted solution was successively washed with water (25ml) twice and a saturated saline (20 ml), and was then dried overanhydrous sodium sulfate. The solvent was distilled away under reducedpressure, and the obtained residue was then purified by silica gelcolumn chromatography (silica gel: eluent; heptane:ethyl acetate=50:50),so as to obtain the title compound (118 mg) in the form of a whitesolid.

<Step 6> Synthesis of2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride

A 4 N hydrochloric acid-1,4-dioxane solution (5 ml) was added to thetert-butyl(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate(116 mg) obtained in (Example 2.7) <Step 5>, and the obtained mixturewas then stirred for 1 hour. Thereafter, the solvent was distilled awayunder reduced pressure, and the title compound (133 mg) was obtained inthe form of a colorless solid.

<Step 7> Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(30 mg) obtained in (Example 1.4) <Step 2> and a free form (20 mg) ofthe 2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride obtained in (Example 2.7) <Step 6>, the title compound (3mg) was obtained in the form of a brown solid by the same method as thatof (Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.8 Synthesis ofN-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid

Using the methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(210 mg) obtained in (Example 1.5) <Step 1>, the title compound (173 mg)was obtained in the form of a whitish brown solid by the same method asthat of (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis ofN-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride (48 mg) obtained in (Example 2.7) <Step 6> and the1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid (50 mg) obtained in (Example 2.8) <Step 1>, the title compound (6.1mg) was obtained in the form of a colorless solid by the same method asthat of (Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.9 Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-6-methylpyridine (273 mg), the title compound (427 mg) wasobtained in the form of a colorless liquid by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (30 mg)obtained in (Example 2.9) <Step 1>, the corresponding sodium salts wereobtained by the same method as that of (Example 2.2) <Step 2> or amethod equivalent thereto. Using the obtained sodium salts (31 mg) andthe 2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride (32 mg) obtained in (Example 2.2) <Step 1>, the titlecompound (22 mg) was obtained in the form of a colorless rubberysubstance by the same method as that of (Example 2.1) <Step 2> or amethod equivalent thereto.

Example 2.10 Synthesis of1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-5-methyl-1,3,4-thiadiazole (320 mg), the title compound(100 mg) was obtained in the form of a yellow solid by the same methodas that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylicacid

Using the methyl1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylate(100 mg) obtained in (Example 2.10) <Step 1>, the title compound (80 mg)was obtained in the form of a light orange solid by the same method asthat of (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylicacid (22 mg) obtained in (Example 2.10) <Step 2>, the title compound (15mg) was obtained in a white amorphous form by the same method as that of(Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.11 Synthesis of4-(6-methoxypyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(6-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-6-methoxypyridine (336 mg), the title compound (263 mg)was obtained in the form of a colorless liquid by the same method asthat of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of sodium4-(6-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl4-(6-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (30 mg)obtained in (Example 2.11) <Step 1>, the title compound (50 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 2.2) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(6-methoxypyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the sodium4-(6-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (31 mg)obtained in (Example 2.11) <Step 2>, the title compound (22 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.12 Synthesis of1-methyl-4-(2-methylthiazol-4-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate

Using 4-bromo-2-methylthiazole (254 mg), the title compound (180 mg) wasobtained in the form of a whitish brown solid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(2-methylthiazol-4-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate (30 mg)obtained in (Example 2.12) <Step 1>, the corresponding sodium salts wereobtained by the same method as that of (Example 2.2) <Step 2> or amethod equivalent thereto. Using the obtained sodium salts (31 mg), thetitle compound (21 mg) was obtained in the form of a white solid by thesame method as that of (Example 2.1) <Step 2> or a method equivalentthereto.

Example 2.13 Synthesis of1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-6-methylpyrazine (309 mg), the title compound (281 mg) wasobtained in the form of a yellow solid by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of sodium1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate

Using the methyl1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate (53 mg)obtained in (Example 2.13) <Step 1>, the title compound (80 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 2.2) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the sodium1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate (27 mg)obtained in (Example 2.13) <Step 2>, the title compound (13 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.14 Synthesis of4-(3-isopropyl-1,2,4-thiadiazol-5-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis ofmethyl-4-(3-isopropyl-1,2,4-thiadiazol-5-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 5-bromo-3-isopropyl-1,2,4-thiadiazole (295 mg), the title compound(140 mg) was obtained in the form of a light orange solid by the samemethod as that of (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis of4-(3-isopropyl-1,2,4-thiadiazol-5-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using themethyl-4-(3-isopropyl-1,2,4-thiadiazol-5-yl)-1-methyl-1H-pyrazole-5-carboxylate(30 mg) obtained in (Example 2.14) <Step 1>, the corresponding sodiumsalts were obtained by the same method as that of (Example 2.2) <Step 2>or a method equivalent thereto. Using the obtained sodium salts (30 mg),the title compound (10 mg) was obtained in the form of a light yellowsolid by the same method as that of (Example 2.1) <Step 2> or a methodequivalent thereto.

Example 2.15 Synthesis of1-methyl-4-(5-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(5-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-5-methylthiazole (318 mg), the title compound (150 mg) wasobtained in the form of a light brown liquid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(5-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using themethyl-1-methyl-4-(5-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate (30mg) obtained by (Example 2.15) <Step 1>, the corresponding sodium saltswere obtained by the same method as that of (Example 2.2) <Step 2> or amethod equivalent thereto. Using the obtained sodium salts (31 mg), thetitle compound (20 mg) was obtained in the form of a white solid by thesame method as that of (Example 2.1) <Step 2> or a method equivalentthereto.

Example 2.16 Synthesis of1-methyl-4-(4-methylpyrimidin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-4-methylpyrimidine (113 mg), the title compound (126 mg)was obtained in the form of a yellow solid by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of sodium1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylate

Using the methyl1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylate (37 mg)obtained in (Example 2.16) <Step 1>, the title compound (56 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 2.2) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of1-methyl-4-(4-methylpyrimidin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the sodium1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylate (19 mg)obtained in (Example 2.16) <Step 2>, the title compound (8.7 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.17 Synthesis of1-methyl-4-(1-methyl-1H-imidazol-4-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(1-methyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate

Using 4-bromo-1-methyl-1H-imidazole (249 mg), the title compound (110mg) was obtained in the form of a white solid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(1-methyl-1H-imidazol-4-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(1-methyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (30 mg)obtained in (Example 2.17) <Step 1>, the corresponding sodium salts wereobtained by the same method as that of (Example 2.2) <Step 2> or amethod equivalent thereto. Using the obtained sodium salts (31 mg), thetitle compound (9.9 mg) was obtained in the form of a white solid by thesame method as that of (Example 2.1) <Step 2> or a method equivalentthereto.

Example 2.18 Synthesis ofN-(2-(2,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl2-(2,5-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate

2-Bromo-1-(2,5-difluorophenyl)ethanone (1.5 g) was added to an ethanol(8.2 ml) solution of methyl 2-aminoisonicotinate (1.0 g), and theobtained mixture was then stirred in a nitrogen atmosphere at 60° C. for18 hours. Thereafter, 2-bromo-1-(2,5-difluorophenyl)ethanone (0.77 g)was added to the reaction solution, and the obtained mixture was thenstirred for 6 hours at the same temperature as described above.Thereafter, the reaction solution was concentrated under reducedpressure, and ethyl acetate (10 ml) was then added to the obtainedresidue. The precipitated solid was collected by filtration, and it waswashed with ethyl acetate (15 ml) and heptane (6 ml) and was then dried,so as to obtain the title compound (2.5 g) in the form of a pink solid.

<Step 2> Synthesis of2-(2,5-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid

Using the methyl2-(2,5-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylate (2.4 g)obtained in (Example 2.18) <Step 1>, the title compound (1.2 g) wasobtained in the form of a light yellow solid by the same method as thatof (Example 2.7) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of tert-butyl(2-(2,5-difluorophenyl)imidazo[1,2-a]pyridin-7-yl)carbamate

Using the 2-(2,5-difluorophenyl)imidazo[1,2-a]pyridine-7-carboxylic acid(1.2 g) obtained in (Example 2.18) <Step 2>, the title compound (786 mg)was obtained in the form of a yellow solid by the same method as that of(Example 2.7) <Step 4> or a method equivalent thereto.

<Step 4> Synthesis of2-(2,5-difluorophenyl)imidazo[1,2-a]pyridin-7-amine hydrochloride

Using the tert-butyl(2-(2,5-difluorophenyl)imidazo[1,2-a]pyridin-7-yl)carbamate (780 mg)obtained in (Example 2.18) <Step 3>, the title compound (886 mg) wasobtained in the form of a light yellow solid by the same method as thatof (Example 2.7) <Step 6> or a method equivalent thereto.

<Step 5> Synthesis of2-(2,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine

Concentrated hydrochloric acid (0.095 ml) and platinum dioxide (0.11 g)were added to a methanol (31 ml) solution of the2-(2,5-difluorophenyl)imidazo[1,2-a]pyridin-7-yl)amine hydrochloride(0.88 g) obtained in (Example 2.18) <Step 4>, and the obtained mixturewas then stirred in a hydrogen atmosphere for 5 hours 30 minutes.Thereafter, platinum dioxide (0.14 g) was added to the reactionsolution, and the obtained mixture was then stirred in a hydrogenatmosphere for 2.5 hours. Thereafter, the reaction solution was filteredwith Celite, and was then washed with methanol (30 ml). The filtrate wasconcentrated under reduced pressure, and the obtained residue was thenpurified by silica gel column chromatography (NH silica gel: eluent;heptane:ethyl acetate=1:4-methylene chloride:methanol=20:1), so as toobtain the title compound (0.44 g) in the form of a colorless solid.

<Step 6> Synthesis ofN-(2-(2,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the2-(2,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine(30 mg) obtained in (Example 2.18) <Step 5> and the1-methyl-4-(5-methyl-1,3,4-thiazol-2-yl)-1H-pyrazole-5-carboxylic acid(32 mg) obtained in (Example 2.10) <Step 2>, the title compound (43 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.19 Synthesis ofN-(3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of (Z)-methyl2-((2,2,2-trifluoro-1-phenylethylidene)amino)isonicotinate

Thionyl chloride (2.2 ml) was added at 0° C. to a pyridine (4.8 ml)solution of 2,2,2-trifluoro-1-phenylethanone (5.1 g) and2-aminopyridine-4-carboxylic acid methyl ester (4.5 g). The temperatureof the reaction solution was increased to room temperature, and thereaction solution was then stirred for 1 hour. Thereafter, the reactionsolution was poured into a 1 N sodium hydroxide aqueous solution, andthe mixed solution was then extracted with ethyl acetate. Organic layerswere gathered, and the gathered organic layer was then dried overanhydrous sodium sulfate. After that, the solvent was distilled awayunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (silica gel: eluent; heptane:ethylacetate=2:1-1:1), so as to obtain the title compound (2.5 g) in the formof a yellow liquid.

<Step 2> Synthesis of methyl3-fluoro-2-phenylimidazo[1,2-a]pyridine-7-carboxylate

Trimethyl phosphite (1.9 ml) was added to an N-methylpyrrolidone (10 ml)solution of the (Z)-methyl2-((2,2,2-trifluoro-1-phenylethylidene)amino)isonicotinate (2.5 g)obtained in (Example 2.19) <Step 1>, and the obtained mixture was thenstirred in microwave at 150° C. for 60 minutes. Thereafter, water wasadded to the reaction solution, and the mixed solution was thenextracted with ethyl acetate. Organic layers were gathered, and thegathered organic layer was then dried over sodium sulfate. The solventwas distilled away under reduced pressure, and the obtained residue wasthen purified by silica gel column chromatography (silica gel: eluent;heptane:ethyl acetate=90:10-50:50), so as to obtain the title compound(1.9 g) in the form of a brown solid.

<Step 3> Synthesis of methyl3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate

A palladium carbon-ethylenediamine complex (0.6 g) was added to amethanol (120 ml) solution of the methyl3-fluoro-2-phenylimidazo[1,2-a]pyridine-7-carboxylate (0.6 g) obtainedin (Example 2.19) <Step 2> and concentrated hydrochloric acid (0.6 ml),and the obtained mixture was then stirred in a hydrogen atmosphere for 7hours. Thereafter, the reaction solution was filtered with Celite, andthe filtrate was then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=2:1-1:1), so as to obtain a crude product(123 mg) containing the title compound in the form of a yellow solid.

<Step 4> Synthesis of3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylicacid

Using the crude product (123 mg) containing the methyl3-fluoro-2-phenylimidazo[1,2-a]pyridine-7-carboxylate obtained in(Example 2.19) <Step 3>, a crude product (200 mg) containing the titlecompound was obtained in the form of a colorless solid by the samemethod as that of (Example 2.7) <Step 3> or a method equivalent thereto.

<Step 5> Synthesis of tert-butyl(3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate

Using the3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylicacid (133 mg) obtained in (Example 2.19) <Step 4>, the title compound(52 mg) was obtained in the form of a colorless solid by the same methodas that of (Example 2.7) <Step 4> or a method equivalent thereto.

<Step 6> Synthesis of3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride

Using the tert-butyl(3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)carbamate(52 mg) obtained in (Example 2.19) <Step 5>, the title compound (41 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 2.7) <Step 6> or a method equivalent thereto.

<Step 7> Synthesis of sodium1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

Sodium hydroxide (3.5 mg) was added to a mixed solution of water (1 ml)and methanol (1 ml) containing the methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(13 mg) obtained in (Example 1.5) <Step 1>, and the obtained mixture wasthen stirred at 70° C. for 30 minutes. Thereafter, the reaction solutionwas subjected to azeotropy with toluene, so as to obtain the titlecompound (20 mg) in the form of a colorless solid.

<Step 8> Synthesis ofN-(3-fluoro-2-phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the3-fluoro-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride (12 mg) obtained in (Example 2.19) <Step 6> and the sodium1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(13 mg) obtained in (Example 2.19) <Step 7>, the title compound (7.5 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 2.1) <Step 2> or a method equivalent thereto.

Example 2.20 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (9.8 mg) obtained in (Example 3.12) <Step 1> and the2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine (8.0mg) obtained in (Example 2.7) <Step 6>, the title compound (8 mg) wasobtained in the form of a white solid by the same method as that of(Example 2.1) <Step 2> or a method equivalent thereto.

The compounds of (Example 2.21) and (Example 2.22) were synthesized bythe same method as that of (Example 2.1) <Step 2> or (Example 2.3), or amethod equivalent thereto, using the corresponding carboxylic acid orsodium salts.

Example 2.211-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 2.221-methyl-4-(4-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

The compounds of (Example 2.23) and (Example 2.24) were synthesized bythe same method as that of (Example 2.3) or a method equivalent thereto,using the corresponding sodium salts of carboxylic acid and the2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-aminehydrochloride obtained in (Example 2.7) <Step 6>.

Example 2.23N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxamideExample 2.24N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamideExample 2.25 Synthesis of1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-4-(thiazol-4-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(thiazol-4-yl)-1H-pyrazole-5-carboxylate

Using 4-bromothiazole (195 mg), the title compound (167 mg) was obtainedin the form of a light yellow solid by the same method as that of(Example 1.1.) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-4-(thiazol-4-yl)-1H-pyrazole-5-carboxamide

Using the methyl 1-methyl-4-(thiazol-4-yl)-1H-pyrazole-5-carboxylate (39mg) obtained in (Example 2.25) <Step 1>, the title compound (18 mg) wasobtained in the form of a brown solid by the same method as that of(Example 2.3) or a method equivalent thereto.

Example 2.26 Synthesis of1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-4-(thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(thiazol-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromothiazole (195 mg), the title compound (133 mg) was obtainedin the form of a brown solid by the same method as that of (Example1.1.) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-4-(thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the methyl 1-methyl-4-(thiazol-2-yl)-1H-pyrazole-5-carboxylate (39mg) obtained in (Example 2.26) <Step 1>, the title compound (16 mg) wasobtained in the form of a brown solid by the same method as that of(Example 2.3) or a method equivalent thereto.

Example 2.27 Synthesis of4-(4-(tert-butyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4-(tert-butyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4-(tert-butyl)thiazole (262 mg), the title compound (190mg) was obtained in the form of a light orange solid by the same methodas that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-(tert-butyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(tert-butyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (30mg) obtained in (Example 2.27) <Step 1>, the title compound (30 mg) wasobtained in the form of a white solid by the same method as that of(Example 2.3) or a method equivalent thereto.

Example 2.28 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine

Using 2-(4-fluorophenyl)-imidazo[1,2-a]pyridin-7-amine hydrochloride(430 mg), the title compound (75 mg) was obtained in the form of a lightorange solid by the same method as that of (Example 2.1) <Step 1> or amethod equivalent thereto.

<Step 2> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(5.0 mg) obtained in (Example 1.3) <Step 1> and the2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amine (3.5mg) obtained in (Example 2.28) <Step 1>, the title compound (1.4 mg) wasobtained in the form of a brown solid by the same method as that of(Example 2.3) or a method equivalent thereto.

Example 2.29 Synthesis ofN-(2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the corresponding hydrochloride (19 mg) of the2-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-amineobtained in (Example 2.28) <Step 1> and the1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid (20 mg) obtained in (Example 2.8) <Step 1>, the title compound (4.6mg) was obtained in the form of a colorless solid by the same method asthat of (Example 2.1) <Step 2> or a method equivalent thereto.

Example 3.1 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.9 g),potassium acetate (1.1 g), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.28 g)were added to a dimethyl sulfoxide (15 ml) solution of methyl4-iodo-1-methyl-1H-pyrazole-5-carboxylate (1.0 g), and the obtainedmixture was then stirred in a nitrogen atmosphere at 100° C. for 45minutes. Thereafter, the reaction solution was subjected to suctionfiltration using Celite, and was then washed with ethyl acetate (100 ml)and water (50 ml). After that, a saturated sodium hydrogen carbonateaqueous solution (50 ml) was added to the filtrate, and a water layerwas separated from an organic layer. The organic layer was successivelywashed with a saturated ammonium chloride aqueous solution (50 ml)twice, water (100 ml) three times, and a saturated saline (100 ml). Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure, and the obtained residue was thenpurified by silica gel column chromatography (silica gel: eluent;heptane:ethyl acetate=90:10-0:100), so as to obtain the title compound(0.30 g) in a yellow amorphous form.

<Step 2> Synthesis of methyl1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate

Using the methyl1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate(1.4 g) obtained in (Example 3.1) <Step 1> and 2-bromo-3-methylpyridine(1.1 g), the title compound (0.54 g) was obtained in the form of ayellow liquid by the same method as that of (Example 1.1) <Step 2> or amethod equivalent thereto.

<Step 3> Synthesis of1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (537 mg)obtained in (Example 3.1) <Step 2>, the title compound (439 mg) wasobtained in the form of a light brown solid by the same method as thatof (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 4> Synthesis of(N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

Phosphorus oxychloride (0.011 ml) was added at 0° C. to a pyridine (0.5ml) solution of the methyl1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid (16 mg)obtained in (Example 3.1) <Step 3> and6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(obtained according to the method described in International PublicationNo. WO2012/076430, p. 80, Example 30-h) (13 mg). The obtained mixturewas stirred at the same temperature as described above for 30 minutes.Thereafter, water was added to the reaction solution, and theprecipitated solid was collected by suction filtration and was thenwashed with methanol, so as to obtain the title compound (18 mg) in theform of a colorless solid.

Example 3.2 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylic acid

Using 2-bromo-5-methylpyrazine (312 mg), the title compound (85 mg) wasobtained in the form of a gray solid by the same methods as those of(Example 3.1) <Step 2> and (Example 1.1) <Step 3>, or methods equivalentthereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid (18 mg) obtained in (Example 3.2) <Step 1>, the title compound (4.4mg) was obtained in the form of a gray solid by the same method as thatof (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.3 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (427 mg)obtained in (Example 2.9) <Step 1>, the title compound (206 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid (18 mg) obtained in (Example 3.3) <Step 1>, the title compound (1.6mg) was obtained in the form of a brown solid by the same method as thatof (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.4 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of sodium4-(4-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4-fluoropyridine (331 mg), the title compound (361 mg) wasobtained in the form of a brown solid by the same methods as those of(Example 3.1) <Step 2> and (Example 2.2) <Step 2>, or methods equivalentthereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the sodium4-(4-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (21 mg)obtained in (Example 3.4) <Step 1>, the title compound (2.8 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.5 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of sodium1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-4-methylpyridine (310 mg), the title compound (300 mg) wasobtained in the form of a brown solid by the same methods as those of(Example 3.1) <Step 2> and (Example 2.2) <Step 2>, or methods equivalentthereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the sodium1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (20 mg)obtained in (Example 3.5) <Step 1>, the title compound (1.3 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.6 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid

Using the methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(210 mg) obtained in (Example 1.5) <Step 1>, the title compound (173 mg)was obtained in the form of a whitish brown solid by the same method asthat of (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid (17 mg) obtained in (Example 3.6) <Step 1>, the title compound (5.0mg) was obtained in the form of a white solid by the same method as thatof (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.7 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of sodium4-(3-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-3-methoxypyridine (339 mg), the title compound (469 mg)was obtained in the form of a gray solid by the same methods as those of(Example 3.1) <Step 2> and (Example 2.2) <Step 2>, or methods equivalentthereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the sodium4-(3-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (21 mg)obtained in (Example 3.7) <Step 1>, the title compound (6.5 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.8 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of sodium4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-5-fluoropyridine (317 mg), the title compound (418 mg) wasobtained in the form of a brown solid by the same methods as those of(Example 3.1) <Step 2> and (Example 2.2) <Step 2>, or methods equivalentthereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the sodium4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (24 mg)obtained in (Example 3.8) <Step 1>, the title compound (1.3 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.9 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-6-methylpyrazine (275 mg), the title compound (228 mg) wasobtained in the form of a light yellow liquid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate (225 mg)obtained in (Example 3.9) <Step 1>, the title compound (184 mg) wasobtained in the form of a white solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid (16 mg) obtained in (Example 3.9) <Step 2>, the title compound (3.1mg) was obtained in the form of an orange solid by the same method asthat of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.10 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylicacid

Using the methyl1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylate(556 mg) obtained in (Example 1.6) <Step 1>, the title compound (160 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylicacid (10 mg) obtained in (Example 3.10) <Step 1>, the title compound(2.0 mg) was obtained in the form of a white solid by the same method asthat of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.11 Synthesis of4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of sodium4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4,6-dimethylpyridine (252 mg), the title compound (191 mg)was obtained in the form of a brown solid by the same methods as thoseof (Example 3.1) <Step 2> and (Example 2.2) <Step 2>, or methodsequivalent thereto.

<Step 2> Synthesis of4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the sodium4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (139 mg)obtained in (Example 3.11) <Step 1>, the title compound (35.4 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.12 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(60 mg) obtained in (Example 1.3) <Step 1>, the title compound (57 mg)was obtained in the form of a beige solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (12 mg) obtained in (Example 3.12) <Step 1>, the title compound(3.5 mg) was obtained in the form of a colorless solid by the samemethod as that of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.13 Synthesis of4-(3-cyanopyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(3-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-chloronicotinonitrile (780 mg), the title compound (2.0 g) wasobtained in the form of a black liquid by the same method as that of(Example 3.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(3-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(3-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (930 mg)obtained in (Example 3.13) <Step 1>, the title compound (456 mg) wasobtained in the form of a brown solid by the same method as that of(Example 3.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of4-(3-cyanopyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(3-cyanopyridin-2-1-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (19 mg) obtained in (Example 3.13) <Step 2>, the title compound (11mg) was obtained in the form of a colorless solid by the same method asthat of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.14 Synthesis of4-(3,6-dimethylpyrazin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(3,6-dimethylpyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 3-chloro-2,5-dimethylpyrazine (0.80 g), the title compound (1.2 g)was obtained in the form of a black liquid by the same method as that of(Example 3.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(3,6-dimethylpyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(3,6-dimethylpyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (930 mg)obtained in (Example 3.14) <Step 1>, the title compound (199 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of4-(3,6-dimethylpyrazin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(3,6-dimethylpyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (19 mg) obtained in (Example 3.14) <Step 2>, the title compound(9.3 mg) was obtained in the form of a colorless solid by the samemethod as that of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.15 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Ethoxycarbonyl isothiocyanate (8.6 g) was added to a 1,4-dioxane (100ml) solution of methyl 2-aminoisonicotinate (9.0 g), and the obtainedmixture was then stirred for 90 minutes. Thereafter, the solvent wasdistilled away under reduced pressure, and the obtained residue was thenadded to a mixed solution of diisopropylethylamine (34 ml), methanol (40ml) and ethanol (70 ml) containing hydroxyamine hydrochloride (22 g).The obtained mixture was stirred under heating at 60° C. for 15 hours.Thereafter, the precipitated solid was collected by filtration, and wasthen washed with ethanol (30 ml), so as to obtain the title compound(9.8 g) in the form of a white solid.

<Step 2> Synthesis of methyl2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

An acetonitrile (560 ml) suspension of tert-butyl nitrile (10.7 g) andcopper(II) bromide (23.3 g) was stirred at 70° C. for 10 minutes.Thereafter, the methyl2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (14.3 g) obtainedin (Example 3.15) <Step 1> was added to the reaction solution at thesame temperature as described above over 20 minutes, and the obtainedmixture was then stirred under heating at 75° C. for 1 hour. Thereafter,ethyl acetate (500 ml) and water (500 ml) were added to the reactionsolution, and insoluble matters were then removed by Celite. After that,the Celite was washed with ethyl acetate (250 ml). The filtrate wasseparated into a water layer and an organic layer, and the water layerwas then extracted with ethyl acetate (250 ml). Organic layers werecombined, and the combined organic layer was successively washed with a5% ammonia aqueous solution (300 ml) twice and water (300 ml). Thesolvent was distilled away under reduced pressure, so as to obtain acrude product of the title compound (11.5 g) in the form of a beigesolid.

<Step 3> Synthesis of2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid

A 1 N sodium hydroxide aqueous solution (150 ml) was added to a methanol(150 ml) suspension of the methyl2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (10 g) obtained in(Example 3.15) <Step 2>, and the obtained mixture was then stirred for30 minutes. Thereafter, about half of the solvent was distilled awayunder reduced pressure, and the residue was then adjusted to pH 4 byaddition of 3 N hydrochloric acid (50 ml). The precipitated solid wascollected by filtration, and was then successively washed with water (50ml) and methyl tert-butyl ether (20 ml). The obtained solid wassubjected to azeotropy with toluene to obtain the title compound (9.0 g)in the form of a white solid.

<Step 4> Synthesis of tert-butyl(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

Triethylamine (0.39 ml), MS4A (1.5 g), and diphenyl phosphate azide(0.18 ml) were added to a tert-butanol (5 ml) solution of the2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (0.17 g) obtainedin (Example 3.15) <Step 3>. The obtained mixture was stirred at roomtemperature for 1 hour, and then at 100° C. for 2 hours. Thereafter,ethyl acetate (50 ml) was added to the reaction solution, and the mixedsolution was then filtered with Celite. The filtrate was washed with asaturated sodium hydrogen carbonate aqueous solution (20 ml), and wasthen dried over anhydrous sodium sulfate. The solvent was distilled awayunder reduced pressure, and the obtained residue was then purified bysilica gel column chromatography (silica gel: eluent; heptane:ethylacetate=75:25-50:50), so as to obtain the title compound (0.15 g) in awhite amorphous form.

<Step 5> Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride

A suspension of 4 N hydrochloric acid-1,4-dioxane (8 ml) and 1,4-dioxane(8 ml) containing the tert-butyl(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (400 mg) obtainedin (Example 3.15) <Step 4> was heated to reflux for 40 minutes.Thereafter, the precipitated solid was collected by filtration, and wasthen washed with 1,4-dioxane (15 ml). The obtained solid was dried toobtain the title compound (279 mg) in the form of a white solid.

<Step 6> Synthesis ofN-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Propylphosphonic anhydride (1.2 ml, a 50% ethyl acetate solution) anddiisopropylethylamine (0.42 ml) were added to a tetrahydrofuran (12 ml)solution of the 4-(4-(difluoromethyl)thiazole-2-yl)-1methyl-1H-pyrazole-5-carboxylic acid (156 mg) obtained in (Example 3.12)<Step 1> and the 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (150 mg) obtained in (Example 3.15) <Step 5>, and theobtained mixture was then stirred under heating at 100° C. for 12 hours.The reaction solution was poured into water (30 ml), and the mixedsolution was then extracted with ethyl acetate (10 ml) three times.Organic layers were combined. The combined organic layer was washed withwater (5 ml), and was then dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (silicagel: eluent; heptane:ethyl acetate=90:10-50:50), so as to obtain thetitle compound (254 mg) in the form of a white solid.

<Step 7> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Dimethoxyethane (1 ml) and water (0.5 ml), which contained theN-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(20 mg) obtained in (Example 3.15) <Step 6>, phenylboronic acid (6.4mg), cesium carbonate (43 mg), and tetrakis(triphenylphosphine)palladium (5.1 mg), were stirred under heating at 100° C. for 3 hours.Thereafter, the reaction solution was cooled to room temperature. Water(20 ml) and ethyl acetate (10 ml) were added to the reaction solution,and an organic layer was separated from a water layer, followed byextraction with ethyl acetate (5 ml) twice. Organic layers werecombined, and the combined organic layer was washed with water (10 ml)and was then dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure, and the obtained residue waspurified by preparative thin-layer chromatography (silica gel: eluent;heptane:ethyl acetate=0:100), so as to obtain the title compound (1.4mg) in the form of a white solid.

Example 3.16 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using 2-methoxyphenylboronic acid (8.0 mg), the title compound (11 mg)was obtained in the form of a yellow solid by the same method as that of(Example 3.15) <Step 7> or a method equivalent thereto.

Example 3.17 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using 3-fluorophenylboronic acid (11 mg), the title compound (1.1 mg)was obtained in the form of a light yellow solid by the same method asthat of (Example 3.15) <Step 7> or a method equivalent thereto.

Example 3.18 Synthesis of4-(4-ethylthiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4-ethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4-ethylthiazole (251 mg), the title compound (126 mg) wasobtained in the form of a light brown solid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-ethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(4-ethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (120 mg)obtained in (Example 3.18) <Step 1>, the title compound (24 mg) wasobtained in the form of a white solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of 1-amino-4-(methoxycarbonyl)pyridin-2(1H)-iminium2,4,6-trimethylbenzenesulfonate

70% Perchloric acid (18.9 ml) was added to a 1,4-dioxane (26 ml)solution of (Z)-ethyl N-(mesitylsulfonyl)oxyacetimidate (11.7 g) at 4°C. over 20 minutes. Thereafter, the reaction solution was stirred at 3°C. for 30 minutes, and it was then poured into water (100 ml). Theprecipitated solid was collected by filtration, and was then washed withwater (45 ml) to obtain a white solid as a crude product. Methyl2-aminoisonicotinate (5 g) was added to methylene chloride (35 ml), andthe obtained mixture was then cooled to 3° C. The obtained crude productwas dissolved in methylene chloride (40 ml), and only an organic layerwas added to a methylene chloride solution of 2-aminoisonicotinate. Theobtained mixture was stirred at 3° C. for 30 minutes. Thereafter, methyltert-butyl ether (50 ml) was added to the reaction solution, and theprecipitated solid was collected by filtration. The collected solid waswashed with methyl tert-butyl ether (20 ml), and was then dried at 45°C., so as to obtain the title compound (10.7 g) in the form of a lightyellow solid.

<Step 4> Synthesis of2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid

Sodium methoxide (10.9 ml, a 5 M methanol solution) and benzaldehyde(3.3 ml) were added to a methanol (100 ml) solution of the1-amino-4-(methoxycarbonyl)pyridin-2(1H)-iminium2,4,6-trimethylbenzenesulfonate (10 g) obtained in (Example 3.18) <Step3>, and the obtained mixture was then stirred for 1 hour. Thereafter,water (5 ml) was added to the reaction solution, and the mixed solutionwas then stirred at 40° C. for 30 minutes. Thereafter, methanol wasdistilled away under reduced pressure, water (50 ml) and methyltert-butyl ether (50 ml) were then added to the residue, followed bystirring the mixture. An organic layer was separated from a water layer,and the water layer was then washed with methyl tert-butyl ether (50 ml)again. The water layer was adjusted to pH 4 by addition of 4 Nhydrochloric acid (10 ml), and a mixed solution of methylene chlorideand methanol (95:5, 50 ml) was then added thereto. Insoluble substanceswere removed by filtration, and an organic layer was then separated froma water layer. The water layer was extracted with a mixed solution ofmethylene chloride and methanol (95:5, 50 ml) twice. Organic layers werethen combined, and the solvent was then distilled away under reducedpressure. The obtained residue was successively triturated with methyltert-butyl ether (50 ml) and methanol (50 ml). The obtained solid waswashed with methanol (20 ml), and was then dried at 50° C. under reducedpressure, so as to obtain the title compound (3.2 g) in the form of abrown solid.

<Step 5> Synthesis of tert-butyl(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

Using the 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (150mg) obtained in (Example 3.18) <Step 4>, the title compound (139 mg) wasobtained in the form of a white solid by the same method as that of(Example 3.15) <Step 4> or a method equivalent thereto.

<Step 6> Synthesis of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride

Using the tert-butyl(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (130 mg) obtainedin (Example 3.18) <Step 5>, the title compound (94 mg) was obtained inthe form of a white solid by the same method as that of (Example 3.15)<Step 5> or a method equivalent thereto.

<Step 7> Synthesis of4-(4-ethylthiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(4-ethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(19 mg) obtained in (Example 3.18) <Step 2> and the2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (17 mg)obtained in (Example 3.18) <Step 6>, the title compound (6.7 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.15) <Step 6> or a method equivalent thereto.

Example 3.19 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-((2S,6R)-2,6-dimethylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

A (2R,6S)-2,6-dimethylmorpholine (0.5 ml) solution of theN-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(30 mg) obtained in (Example 3.15) <Step 6> was heated by microwave at150° C. for 1 hour. Thereafter, the reaction solution was diluted withethyl acetate (20 ml). The diluted solution was washed with water (15ml) twice and a saturated saline (10 ml), and was then dried overanhydrous sodium sulfate. The solvent was distilled away under reducedpressure, and the obtained residue was then purified by silica gelcolumn chromatography (silica gel: eluent; heptane:ethyl acetate=25:75),so as to obtain the title compound (27 mg) in the form of a light yellowsolid.

Example 3.20 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(8.0 mg) obtained in (Example 3.15) <Step 7> and N-chlorosuccinimide(2.1 mg), the title compound (1.1 mg) was obtained in the form of alight yellow solid by the same method as that of (Example 1.4) <Step 1>or a method equivalent thereto.

Example 3.21 Synthesis ofN-(5-chloro-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(2-methoxyphenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(5 mg) obtained in (Example 3.16) and N-chlorosuccinimide (1.7 mg), thetitle compound (1.2 mg) was obtained in the form of an orange solid bythe same method as that of (Example 1.4) <Step 1> or a method equivalentthereto.

Example 3.22 Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.5 ml) was added to a1,4-dioxane (19 ml) solution of methyl4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1.9 g),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.15 g),Tris(dibenzylideneacetone)dipalladium(0) (0.16 g), and triethylamine(3.7 ml). The obtained mixture was stirred in a nitrogen atmosphere at100° C. for 30 minutes. Thereafter,4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 ml) was added to thereaction solution, and the obtained mixture was then stirred for 30minutes at the same temperature as described above. Thereafter, anaqueous solution (3.9 ml) of potassium carbonate (3.6 g) and a1,4-dioxane (4 ml) solution of 4-chloro-2,5-dimethylpyrimidine (1.0 g)were successively added to the reaction solution, and the obtainedmixture was then stirred at the same temperature as described above for1 hour. Thereafter, water was added to the reaction solution, and themixed solution was extracted with ethyl acetate and was then dried overanhydrous sodium sulfate. The solvent was distilled away under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (silica gel: eluent; heptane:ethyl acetate=3:1-1:1-0:1),so as to obtain the title compound (1.9 g) in the form of an orangeliquid.

<Step 2> Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Sodium hydroxide (0.31 g) was added to a mixed solution of methanol (15ml) and water (15 ml) containing the methyl4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.9g) obtained in (Example 3.22) <Step 1>, and the obtained mixture wasthen stirred at 50° C. for 1 hour. Thereafter, methanol was distilledaway from the reaction solution under reduced pressure, and the residuewas then adjusted to pH 5-6 by addition of 1 N hydrochloric acid.Thereafter, water was distilled away under reduced pressure. Theobtained residue was washed with methylene chloride, and the filtratewas then concentrated under reduced pressure, so as to obtain the titlecompound (0.94 g) in the form of a yellow solid.

<Step 3> Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

An N-methylpyrrolidone (7.7 ml) solution of the4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(715 mg) obtained in (Example 3.22) <Step 2>,6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(obtained according to the method described in International PublicationNo. WO2012/076430, p. 80, Example 30-h) (815 mg),2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium (2.34 g), and diisopropylethylamine (2.69 ml) was stirredat 80° C. for 3 hours. Thereafter, water was added to the reactionsolution, and the mixed solution was then extracted with ethyl acetate.Organic layers were combined, and the combined organic layer was thendried over anhydrous sodium sulfate. Subsequently, the solvent wasdistilled away under reduced pressure, and the obtained residue was thenpurified by silica gel column chromatography (NH silica gel: eluent;heptane:ethyl acetate=3:1-1:1). The obtained fraction was concentratedunder reduced pressure. The obtained residue (solid) was triturated withmethanol to obtain the title compound (377 mg) in the form of acolorless solid.

Example 3.23 Synthesis of4-(5-cyanopyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(5-cyanopyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (1.0 g) and6-bromonicotinonitrile (0.73 g), the title compound (72 mg) was obtainedin the form of a colorless solid by the same method as that of (Example3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-cyanopyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(5-cyanopyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (20 mg) obtained in (Example 3.23) <Step 1>, the title compound(4.3 mg) was obtained in the form of a colorless solid by the samemethod as that of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.24 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylate

Using 3-chloro-4-methylpyridazine (0.41 g), a crude product (2.0 g)containing the title compound was obtained in the form of a black liquidby the same method as that of (Example 3.22) <Step 1> or a methodequivalent thereto.

<Step 2> Synthesis of1-methyl-4-(4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylate (1.06 g)obtained in (Example 3.24) <Step 1>, the title compound (300 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(4-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylicacid (37 mg) obtained in (Example 3.24) <Step 2>, the title compound(5.4 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.25 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate

Using 4-chloro-2-methylpyrimidine (0.94 g), the title compound (1.26 g)was obtained in the form of a yellow oily substance by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (1.26 g)obtained in (Example 3.25) <Step 1>, the title compound (682 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylicacid (300 mg) obtained in (Example 3.25) <Step 2>, the title compound(284 mg) was obtained in the form of a gray solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.26 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-bromo-2-methoxypyrimidine (1.38 g), the title compound (1.73 g)was obtained in the form of an orange oily substance by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.73 g)obtained in (Example 3.26) <Step 1>, the title compound (308 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (270 mg) obtained in (Example 3.26) <Step 2>, the title compound(200 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.27 Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-5-fluoro-2-methoxypyrimidine (1.5 g), the title compound(1.6 g) was obtained in the form of a light yellow liquid by the samemethod as that of (Example 3.22) <Step 1> or a method equivalentthereto.

<Step 2> Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(1.6 g) obtained in (Example 3.27) <Step 1>, the title compound (0.65 g)was obtained in the form of a colorless solid by the same method as thatof (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (381 mg) obtained in (Example 3.27) <Step 2>, the title compound(62.6 mg) was obtained in the form of a light yellow solid by the samemethod as that of (Example 3.22) <Step 3> or a method equivalentthereto.

Example 3.28 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(3-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-chloro-3-methoxypyrazine (2.11 g), the title compound (2.69 g)was obtained in the form of a light brown oily substance by the samemethod as that of (Example 3.22) <Step 1> or a method equivalentthereto.

<Step 2> Synthesis of4-(3-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(3-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.6 g)obtained in (Example 3.28) <Step 1>, the title compound (0.44 g) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(3-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (372 mg) obtained in (Example 3.28) <Step 2>, the title compound(89 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.29 Synthesis of4-(5-chloropyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-chloropyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4,5-dichloropyrimidine (0.54 g), the title compound (0.46 g) wasobtained in the form of a brown liquid by the same method as that of(Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-chloropyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(5-chloropyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.45 g)obtained in (Example 3.29) <Step 1>, the title compound (0.30 g) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(5-chloropyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(5-chloropyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (270 mg) obtained in (Example 3.29) <Step 2>, the title compound(260 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.30 Synthesis of4-(2,6-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(2,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-2,6-dimethylpyrimidine (1.17 g), the title compound (2.05g) was obtained in the form of an orange liquid by the same method asthat of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(2,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(2,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (2.05g) obtained in (Example 3.30) <Step 1>, the title compound (666 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(2,6-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(2,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(300 mg) obtained in (Example 3.30) <Step 2>, the title compound (290mg) was obtained in the form of a brown solid by the same method as thatof (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.31 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-methoxy-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(6-methoxy-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-6-methoxy-5-methylpyrimidine (1.16 g), the title compound(2.72 g) was obtained in the form of an orange oily substance by thesame method as that of (Example 3.22) <Step 1> or a method equivalentthereto.

<Step 2> Synthesis of4-(6-methoxy-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(6-methoxy-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(2.39 g) obtained in (Example 3.31) <Step 1>, the title compound (814mg) was obtained in the form of a colorless solid by the same method asthat of (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-methoxy-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(6-methoxy-5-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (300 mg) obtained in (Example 3.31) <Step 2>, the title compound(263 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.32 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-iodo-3-methylpyrazine (1.2 g), the title compound (1.2 g) wasobtained in the form of a green liquid by the same method as that of(Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylate (1.2 g)obtained in (Example 3.32) <Step 1>, the title compound (0.55 g) wasobtained in the form of a brown solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(3-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid (420 mg) obtained in (Example 3.32) <Step 2>, the title compound(179 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.33 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate

Using 4-chloro-5-methylpyrimidine (0.52 g), the title compound (0.16 g)was obtained in the form of a brown oily substance by the same method asthat of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (155 mg)obtained in (Example 3.33) <Step 1>, the title compound (175 mg) wasobtained in the form of a light yellow solid by the same method as thatof (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(5-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylicacid (129 mg) obtained in (Example 3.33) <Step 2>, the title compound(13.3 mg) was obtained in the form of a colorless solid by the samemethod as that of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.34 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-5-methoxypyrimidine (0.31 g), the title compound (0.43 g)was obtained in the form of a white solid by the same method as that of(Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl(4-(5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.42 g)obtained in (Example 3.34) <Step 1>, the title compound (290 mg) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(5-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (265 mg) obtained in (Example 3.34) <Step 2>, the title compound(220 mg) was obtained in the form of a light brown solid by the samemethod as that of (Example 3.22) <Step 3> or a method equivalentthereto.

Example 3.35 Synthesis of4-(5,6-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-5,6-dimethylpyrimidine (94 mg), the title compound (71mg) was obtained in the form of a white solid by the same method as thatof (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(5,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.7g) obtained in (Example 3.35) <Step 1>, the title compound (1.2 g) wasobtained in the form of a light yellow solid by the same method as thatof (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(5,6-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(5,6-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(400 mg) obtained in (Example 3.35) <Step 2>, the title compound (260mg) was obtained in the form of a light brown solid by the same methodas that of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.36 Synthesis of4-(5-fluoro-2-methylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-fluoro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-5-fluoro-2-methylpyrimidine (0.75 g), the title compound(1.35 g) was obtained in the form of an orange liquid by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-fluoro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(5-fluoro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(1.35 g) obtained in (Example 3.36) <Step 1>, the title compound (0.869g) was obtained in the form of a light brown solid by the same method asthat of (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(5-fluoro-2-methylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(5-fluoro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (450 mg) obtained in (Example 3.36) <Step 2>, the title compound(350 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.37 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate

Using 4-chloro-2,5,6-trimethylpyrimidine (1.0 g), the title compound(1.1 g) was obtained in the form of a brown liquid by the same method asthat of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate(1.1 g) obtained in (Example 3.37) <Step 1>, the title compound (0.48 g)was obtained in the form of a colorless solid by the same method as thatof (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(2,5,6-trimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid(373 mg) obtained in (Example 3.37) <Step 2>, the title compound (182mg) was obtained in the form of a light brown solid by the same methodas that of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.38 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-5-fluoro-6-methylpyrimidine (150 mg), the title compound(103 mg) was obtained in the form of a yellow liquid by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(101 mg) obtained in (Example 3.38) <Step 1>, the title compound (71.5mg) was obtained in the form of a white solid by the same method as thatof (Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(5-fluoro-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (66 mg) obtained in (Example 3.38) <Step 2>, the title compound (38mg) was obtained in the form of a brown solid by the same method as thatof (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.39 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate

Using 4-chloro-6-methylpyrimidine (1.88 g), the title compound (665 mg)was obtained in the form of a light brown solid by the same method asthat of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (655 mg)obtained in (Example 3.39) <Step 1>, the title compound (564 mg) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylicacid (346 mg) obtained in (Example 3.39) <Step 2>, the title compound(392 mg) was obtained in the form of a black solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.40 Synthesis of4-(2,6-dimethoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(2,6-dimethoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-chloro-2,6-dimethoxypyrimidine (1.28 g), the title compound(2.53 g) was obtained in the form of an orange liquid by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(2,6-dimethoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(2,6-dimethoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (2.53g) obtained in (Example 3.40) <Step 1>, the title compound (988 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(2,6-dimethoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(2,6-dimethoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(360 mg) obtained in (Example 3.40) <Step 2>, the title compound (266mg) was obtained in the form of a brown solid by the same method as thatof (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.41 Synthesis of4-(5-chloro-2-methylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-chloro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4,5-dichloro-2-methylpyrimidine (180 mg), the title compound (50mg) was obtained in the form of a yellow liquid by the same method asthat of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-chloro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(5-chloro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(50 mg) obtained in (Example 3.41) <Step 1>, the title compound (32 mg)was obtained in the form of a brown solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(5-chloro-2-methylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(5-chloro-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (21 mg) obtained in (Example 3.41) <Step 2>, the title compound(1.3 mg) was obtained in the form of a light brown solid by the samemethod as that of (Example 3.22) <Step 3> or a method equivalentthereto.

Example 3.42 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(6-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-chloro-6-methoxypyrazine (1.0 g), the title compound (1.7 g) wasobtained in the form of a yellow liquid by the same method as that of(Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(6-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(6-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.5 g)obtained in (Example 3.42) <Step 1>, the title compound (0.44 g) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(6-methoxypyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (380 mg) obtained in (Example 3.42) <Step 2>, the title compound(62 mg) was obtained in the form of a yellow solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.43 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-chloro-4-methylpyrimidine (0.92 g), the title compound (1.0 g)was obtained in the form of an orange liquid by the same method as thatof (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylate (1.0 g)obtained in (Example 3.43) <Step 1>, the title compound (0.40 g) wasobtained in the form of a brown solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-5-carboxylicacid (346 mg) obtained in (Example 3.43) <Step 2>, the title compound(398 mg) was obtained in the form of a brown solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.44 Synthesis of4-(4,6-dimethylpyrimidin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4,6-dimethylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-chloro-4,6-dimethylpyrimidine (1.6 g), the title compound (0.47g) was obtained in the form of an orange liquid by the same method asthat of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(4,6-dimethylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(4,6-dimethylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (460mg) obtained in (Example 3.44) <Step 1>, the title compound (288 mg) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of4-(4,6-dimethylpyrimidin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4,6-dimethylpyrimidin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(250 mg) obtained in (Example 3.44) <Step 2>, the title compound (280mg) was obtained in the form of a brown solid by the same method as thatof (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.45 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylate

Using 3-chloro-6-methylpyridazine (0.94 g), the title compound (0.65 g)was obtained in the form of an orange oily substance by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylate (0.6 g)obtained in (Example 3.45) <Step 1>, the title compound (0.35 g) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylicacid (170 mg) obtained in (Example 3.45) <Step 2>, the title compound(186 mg) was obtained in the form of a white solid by the same method asthat of (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.46 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylate

Using 3-chloro-5-methylpyridazine (0.94 g), the title compound (0.45 g)was obtained in the form of an orange oily substance by the same methodas that of (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylate (400 mg)obtained in (Example 3.46) <Step 1>, the title compound (49 mg) wasobtained in the form of a red solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(5-methylpyridazin-3-yl)-1H-pyrazole-5-carboxylicacid (50 mg) obtained in (Example 3.46) <Step 2>, the title compound (51mg) was obtained in the form of a white solid by the same method as thatof (Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.47 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyridazin-3-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(pyridazin-3-yl)-1H-pyrazole-5-carboxylate

Using 3-chloropyridazine (0.5 g), the title compound (0.3 g) wasobtained in the form of a red oily substance by the same method as thatof (Example 3.22) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(pyridazin-3-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl 1-methyl-4-(pyridazin-3-yl)-1H-pyrazole-5-carboxylate(300 mg) obtained in (Example 3.47) <Step 1>, the title compound (96 mg)was obtained in the form of a red solid by the same method as that of(Example 3.22) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyridazin-3-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(pyridazin-3-yl)-1H-pyrazole-5-carboxylic acid (90mg) obtained in (Example 3.47) <Step 2>, the title compound (98 mg) wasobtained in the form of a white solid by the same method as that of(Example 3.22) <Step 3> or a method equivalent thereto.

Example 3.48 Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(1-methyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(1-methyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (50 mg)obtained in (Example 2.17) <Step 1>, the corresponding sodium salts wereobtained by the same method as that of (Example 2.2) <Step 2> or amethod equivalent thereto. Using the obtained sodium salts (50 mg), thetitle compound (12 mg) was obtained in the form of a brown solid by thesame method as that of (Example 3.22) <Step 3> or a method equivalentthereto.

Example 3.49 Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis ofN-(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (2.3 g) obtained in (Example 4.24) <Step 1> and the4-(2,5-dimethylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid (2.0 g)obtained in (Example 3.22) <Step 2>, the title compound (2.3 g) wasobtained in the form of a beige solid by the same method as that of(Example 3.22) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(500 mg) obtained in (Example 3.49) <Step 1> and 3-pyridineboronic acid(414 mg), the title compound (15 mg) was obtained in the form of acolorless solid by the same method as that of (Example 3.15) <Step 7> ora method equivalent thereto.

Example 3.50 Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-(o-tolyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(100 mg) obtained in (Example 3.49) <Step 1> and o-tolylboronic acid (55mg), the title compound (24 mg) was obtained in the form of a whitesolid by the same method as that of (Example 3.15) <Step 7> or a methodequivalent thereto.

Using the corresponding carboxylic acid or sodium salts, the compoundsof (Example 3.51) to (Example 3.53) were synthesized by the same methodas that of (Example 3.1) <Step 4> or a method equivalent thereto.

Example 3.51N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-carboxamideExample 3.52N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamideExample 3.534-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide2,2,2-trifluoroacetate Example 3.54 Synthesis of4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of tert-butyl(6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

Using the tert-butyl(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (180 mg)obtained in (Example 4.11) <Step 4> and 4-fluoroboronic acid (114 mg),the title compound (123 mg) was obtained in the form of a white solid bythe same method as that of (Example 3.15) <Step 7> or a methodequivalent thereto.

<Step 2> Synthesis of6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the tert-butyl(6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate(105 mg) obtained in (Example 3.54) <Step 1>, the title compound (34 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 3.15) <Step 5> or a method equivalent thereto.

<Step 3> Synthesis of4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the6-fluoro-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (7 mg)obtained in (Example 3.54) <Step 2> and the sodium4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (11 mg)obtained in (Example 3.11) <Step 1>, the title compound (1.4 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 4.1 Synthesis of(S)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

An (S)-2-methylpyrrolidine (0.5 ml) solution of theN-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(30 mg) synthesized in (Example 3.15) <Step 6> was stirred undermicrowave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (20ml) was added to the reaction solution, and the mixed solution wassuccessively washed with water (15 ml) twice and with a saturated saline(10 ml) once, and was then dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (silicagel: eluent; heptane:ethyl acetate=40:60), so as to obtain the titlecompound (13 mg) in the form of a light yellow solid.

Example 4.2 Synthesis of(S)-4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the(S)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(11 mg) obtained in (Example 4.1) and N-chlorosuccinimide (3.5 mg), thetitle compound (5.5 mg) was obtained in the form of a white solid by thesame method as that of (Example 1.4) <Step 1> or a method equivalentthereto.

Example 4.3 Synthesis of(S)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of(S)-2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(750 mg) obtained in (Example 3.15) <Step 5>, the title compound (450mg) was obtained in the form of a light yellow solid by the same methodas that of (Example 4.1) or a method equivalent thereto.

<Step 2> Synthesis of(S)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide

Oxalyl chloride (0.52 ml) and N,N-dimethylformamide (5 μl) were added toa methylene chloride (5 ml) solution of the1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylicacid (160 mg) obtained in (Example 3.10) <Step 1>, and the obtainedmixture was then stirred at room temperature for 1 hour. Thereafter, thesolvent was distilled away under reduced pressure, and a crude product(175 mg) was obtained in the form of a yellow liquid. To a methylenechloride (1 ml) solution of the obtained crude product (42 mg), pyridine(35 μl) and a methylene chloride (1 ml) solution of the(S)-2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(26 mg) obtained in (Example 4.3) <Step 1>, and the obtained mixture wasthen stirred for 16 hours. Thereafter, the solvent was distilled awayunder reduced pressure, and the obtained residue was then purified byLC/MS, so as to obtain the title compound (36 mg) in the form of a whitesolid.

Example 4.4 Synthesis of(S)-1-methyl-4-(4-methylpyridin-2-yl)-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate

Using 2-bromo-4-methylpyridine (273 mg), the title compound (233 mg) wasobtained in the form of a yellow liquid by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid

Using the methyl1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (230 mg)obtained in (Example 4.4) <Step 1>, the title compound (121 mg) wasobtained in the form of a white solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of(S)-1-methyl-4-(4-methylpyridin-2-yl)-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.4) <Step 2>, the title compound (28 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.5 Synthesis of(S)-4-(4-methoxypyridin-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4-methoxypyridine (298 mg), the title compound (186 mg)was obtained in the form of a yellow liquid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (185 mg)obtained in (Example 4.5) <Step 1>, the title compound (138 mg) wasobtained in the form of a red solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of(S)-4-(4-methoxypyridin-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.5) <Step 2>, the title compound (18 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.6 Synthesis of(S)-1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.9) <Step 2>, the title compound (21 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.7 Synthesis of(S)-1-methyl-4-(6-methylpyridin-2-yl)-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.3) <Step 2>, the title compound (17 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.8 Synthesis of(S)-4-(4,6-dimethylpyridin-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4,6-dimethylpyridine (295 mg), the title compound (310 mg)was obtained in the form of a yellow liquid by the same method as thatof (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (310 mg)obtained in (Example 4.8) <Step 1>, the title compound (141 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 3> Synthesis of(S)-4-(4,6-dimethylpyridin-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.8) <Step 2>, the title compound (10 mg) wasobtained in the form of a yellow solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.9 Synthesis of(S)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(90 mg) obtained in (Example 1.4) <Step 2>, the title compound (64 mg)was obtained in the form of a white solid by the same method as that of(Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis of(S)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.9) <Step 1>, the title compound (21 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.10 Synthesis of(S)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(trifluoromethylthiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid

Using the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(210 mg) obtained in (Example 1.5) <Step 1>, the title compound (173 mg)was obtained in the form of a whitish brown solid by the same method asthat of (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis of(S)-1-methyl-N-(2-(2-methylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(trifluoromethylthiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.10) <Step 1>, the title compound (14 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.11 Synthesis of(R)—N-(6-fluoro-2-(2-(trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl2-amino-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Using methyl 2-amino-5-fluoroisonicotinate, the title compound wasobtained in the form of a yellow solid by the same method as that of(Example 3.15) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of methyl2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Using the methyl2-amino-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (10 g)obtained in (Example 4.11) <Step 1>, the title compound (5.5 g) wasobtained in the form of a brown solid by the same method as that of(Example 3.15) <Step 2> or a method equivalent thereto.

<Step 3> Synthesis of2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid

Using the methyl2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (5.56 g)obtained in (Example 4.11) <Step 2>, the title compound (2.15 g) wasobtained in the form of a brown solid by the same method as that of(Example 3.15) <Step 3> or a method equivalent thereto.

<Step 4> Synthesis of tert-butyl(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

Using the 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid (2.15 g) obtained in (Example 4.11) <Step 3>, the title compound(2.52 g) was obtained in the form of an orange solid by the same methodas that of (Example 3.15) <Step 3> or a method equivalent thereto.

<Step 5> Synthesis of (R)-tert-butyl(6-fluoro-2-(2-(trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

A 1,4-dioxane (5.5 ml) solution of the tert-butyl(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (110 mg)obtained in (Example 4.11) <Step 4>,tris(dibenzylideneacetone)dipalladium(0) (48 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61 mg), cesiumcarbonate (162 mg), and (R)-2-(trifluoromethyl)pyrrolidine (231 mg) waspurged with nitrogen gas, and it was then stirred under heating at 110°C. for 12 hours. Thereafter, water and ethyl acetate were added to thereaction solution, and the mixed solution was then extracted with ethylacetate (10 ml) three times. The solvent was distilled away underreduced pressure, and the obtained residue was then purified by silicagel column chromatography (silica gel: eluent; heptane:ethylacetate=5:1-1:1), so as to obtain the title compound (75 mg) in the formof a white solid.

<Step 6> Synthesis of(R)-6-fluoro-2-(2-(trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the (R)-tert-butyl(6-fluoro-2-(2-(trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate(73 mg) obtained in (Example 4.11) <Step 5>, the title compound (41 mg)was obtained in the form of a white solid by the same method as that of(Example 3.15) <Step 5> or a method equivalent thereto.

<Step 7> Synthesis of(R)—N-(6-fluoro-2-(2-(trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid (3.8 mg) obtained in (Example 3.3) <Step 2> and the(R)-6-fluoro-2-(2-(trifluoromethyl)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(5 mg) obtained in (Example 4.11) <Step 6>, the title compound (1.1 mg)was obtained in the form of a brown solid by the same method as that of(Example 3.1) <Step 4> or a method equivalent thereto.

Example 4.12 Synthesis of(R)-4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using (R)-3-fluoropyrrolidine hydrochloride (179 mg), the title compound(4.4 mg) was obtained in the form of a light brown solid by the samemethod as that of (Example 4.1) or a method equivalent thereto.

Example 4.13 Synthesis of(R)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of(R)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(700 mg) obtained in (Example 3.15) <Step 5> and (R)-3-fluoropyrrolidinehydrochloride (5 g), the title compound (160 mg) was obtained in theform of a beige solid by the same method as that of (Example 4.1) or amethod equivalent thereto.

<Step 2> Synthesis of(R)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.10) <Step 1> and the(R)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.13) <Step 1>, the title compound (13 mg)was obtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.14 Synthesis of(R)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.9) <Step 1> and the(R)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.13) <Step 1>, the title compound (19 mg)was obtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.15 Synthesis of(S)-4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using (S)-3-fluoropyrrolidine hydrochloride (179 mg), the title compound(4.3 mg) was obtained in the form of a light brown solid by the samemethod as that of (Example 4.1) or a method equivalent thereto.

Example 4.16 Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of(S)-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(700 mg) obtained in (Example 3.15) <Step 5> and (R)-3-fluoropyrrolidinehydrochloride (4.5 g), the title compound (240 mg) was obtained in theform of a white solid by the same method as that of (Example 4.1) or amethod equivalent thereto.

<Step 2> Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.10) <Step 1> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (9.3 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.17 Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.4) <Step 2> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (7.6 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.18 Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.5) <Step 2> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (1.0 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.19 Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.9) <Step 2> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (3.2 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.20 Synthesis of(S)-4-(4,6-dimethylpyridin-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.8) <Step 2> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (4.8 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.21 Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.3) <Step 2> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (1.9 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.22 Synthesis of(S)—N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-(trifluoromethyl)methylthiazol-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.10) <Step 1> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (11 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.23 Synthesis of(S)-4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.9) <Step 1> and the(S)-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(20 mg) obtained in (Example 4.16) <Step 1>, the title compound (47 mg)was obtained by the same method as that of (Example 4.3) <Step 2> or amethod equivalent thereto.

Example 4.24 Synthesis of(S)-4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride

Using the tert-butyl(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (200 mg)obtained in (Example 4.11) <Step 4>, the title compound (154 mg) wasobtained in the form of a white solid by the same method as that of(Example 3.15) <Step 5> or a method equivalent thereto.

<Step 2> Synthesis of(S)-6-fluoro-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the 2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (100 mg) obtained in (Example 4.24) <Step 1> and(S)-3-fluoropyrrolidine hydrochloride (469 mg), the title compound (15.5mg) was obtained in the form of a beige solid by the same method as thatof (Example 4.1) or a method equivalent thereto.

<Step 3> Synthesis of(S)-4-(4,6-dimethylpyridin-2-yl)-N-(6-fluoro-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the(S)-6-fluoro-2-(3-fluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine(11 mg) obtained in (Example 4.24) <Step 2> and the4-(4,6-dimethylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (10mg) obtained in (Example 4.8) <Step 2>, the title compound (3.0 mg) wasobtained in the form of a whitish brown solid by the same method as thatof (Example 3.1) <Step 4> or a method equivalent thereto.

Example 4.25 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using pyrrolidine (0.4 ml), the title compound (18 mg) was obtained inthe form of a light yellow solid by the same method as that of (Example4.1) or a method equivalent thereto.

Example 4.26 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(15 mg) obtained in (Example 4.25) and N-chlorosuccinimide (5.4 mg), thetitle compound (2.3 mg) was obtained in the form of a light yellow solidby the same method as that of (Example 1.4) <Step 1> or a methodequivalent thereto.

Example 4.27 Synthesis of1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride

The tert-butyl (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (75mg) obtained in (Example 3.15) <Step 4> and pyrrolidine (1 ml) werestirred under microwave heating at 150° C. for 1 hour. Thereafter, ethylacetate (10 ml) and water (3 ml) were added to the reaction solution. Anorganic layer was separated, and was then dried over anhydrous sodiumsulfate. The solvent was distilled away under reduced pressure.Thereafter, potassium hydroxide (134 mg) was added to an ethanol (2 ml)solution of the obtained residue, and the obtained mixture was thenheated to reflux for 16 hours. Thereafter, the solvent was distilledaway under reduced pressure, and potassium hydroxide (134 mg) was addedto an ethylene glycol (2 ml) solution of the obtained residue, followedby heating the obtained mixture at 155° C. for 2 hours. The solvent wasdistilled away under reduced pressure, and ethyl acetate (10 ml) andwater (3 ml) were then added to the obtained residue. An organic layerwas separated, and was then dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (silicagel: eluent; heptane:ethyl acetate=50:50-0:100) to obtain a crudeproduct. The obtained crude product was dissolved in 4 N hydrochloricacid-ethyl acetate (1 ml), and the precipitated solid was then collectedby filtration, so as to obtain the title compound (16 mg) in the form ofa yellow solid.

<Step 2> Synthesis of1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxylate(20 mg) obtained in (Example 1.6) <Step 1> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(14 mg) obtained in (Example 4.27) <Step 1>, the title compound (5.2 mg)was obtained in the form of a light brown solid by the same method asthat of (Example 3.15) <Step 6> or a method equivalent thereto.

Example 4.28 Synthesis of4-(4-methoxypyridin-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine

Using the 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride(90 mg) obtained in (Example 3.15) <Step 5> and pyrrolidine (0.6 ml),the title compound (64 mg) was obtained in the form of a light brownsolid by the same method as that of (Example 4.1) or a method equivalentthereto.

<Step 2> Synthesis of4-(4-methoxypyridin-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(4-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.5) <Step 2> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (24 mg)obtained in (Example 4.28) <Step 1>, the title compound (19 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.29 Synthesis of1-methyl-4-(6-methylpyrazin-2-yl)-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.9) <Step 2> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (35 mg)obtained in (Example 4.28) <Step 1>, the title compound (9.3 mg) wasobtained in the form of a colorless solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.30 Synthesis of1-methyl-4-(4-methylpyridin-2-yl)-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyrazin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.4) <Step 2> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (22 mg)obtained in (Example 4.28) <Step 1>, the title compound (14 mg) wasobtained in the form of a light brown solid by the same method as thatof (Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.31 Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 3.3) <Step 2> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (31 mg)obtained in (Example 4.28) <Step 1>, the title compound (18 mg) wasobtained in the form of a light yellow solid by the same method as thatof (Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.32 Synthesis of4-(4,6-dimethylpyridin-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.8) <Step 2> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (21 mg)obtained in (Example 4.28) <Step 1>, the title compound (3.4 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.33 Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid obtained in (Example 4.9) <Step 1> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (15 mg)obtained in (Example 4.28) <Step 1>, the title compound (10 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.34 Synthesis of1-methyl-N-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-(trifluoromethyl)methylthiazol-2-yl)-1H-pyrazole-5-carboxylicacid obtained in (Example 4.10) <Step 1> and the2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (12 mg)obtained in (Example 4.28) <Step 1>, the title compound (5.1 mg) wasobtained in the form of a white solid by the same method as that of(Example 4.3) <Step 2> or a method equivalent thereto.

Example 4.35 Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

A pyrrolidine (3 ml) solution of theN-(2-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(500 mg) obtained in (Example 3.49) <Step 1> was heated at 100° C. for 5hours. Thereafter, the reaction solution was diluted with water, and wasthen washed with ethyl acetate. The water layer was adjusted to neutralwith 1 N hydrochloric acid, and was then extracted with ethyl acetate.The solvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (NH silicagel: eluent; heptane:ethyl acetate=75:25-0:100) to obtain a crudeproduct. Methanol was added to the obtained crude product, followed bycollection by filtration, so as to obtain the title compound (82 mg) inthe form of a yellow solid.

Example 4.36 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-N-((2S,6R)-2,6-dimethylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(24 mg) obtained in (Example 3.19) and N-chlorosuccinimide (7.1 mg), thetitle compound (12 mg) was obtained in the form of a white solid by thesame method as that of (Example 1.4) <Step 1> or a method equivalentthereto.

Example 5.1 Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid

10% Palladium-carbon (3 g) and concentrated hydrochloric acid (3.1 ml)were added to a mixed solution of methanol (200 ml) and methylenechloride (150 ml) containing the2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (3 g) obtainedin (Example 3.18) <Step 4>, and the obtained mixture was then stirred ina hydrogen atmosphere for 15 hours. Thereafter, the reaction solutionwas heated to 40° C., and then, it was further stirred for 4 hours.Thereafter, the reaction solution was filtered with Celite, and was thenwashed with methanol. The filtrate was concentrated under reducedpressure, and the solvent was then distilled away. After that, methanol(20 ml) and a 4 N sodium hydroxide aqueous solution (9 ml) were added tothe residue, and the obtained mixture was then stirred at 50° C. for 30minutes. Thereafter, the solvent was distilled away under reducedpressure, and a 1 N hydrochloric acid aqueous solution (9 ml) was thenadded to the residue. The generated solid was collected by filtration,and was then washed with water (10 ml). The obtained solid was driedunder reduced pressure at 45° C. for 15 hours, so as to obtain the titlecompound (2.4 g) in the form of a white solid.

<Step 2> Synthesis of tert-butyl(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamate

Using the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid (2 g) obtained in (Example 5.1) <Step 1>, the title compound (2 g)was obtained in the form of a white solid by the same method as that of(Example 3.18) <Step 5> or a method equivalent thereto.

<Step 3> Synthesis of2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride

Using the tert-butyl(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carbamate(1.9 g) obtained in (Example 5.1) <Step 2>, the title compound (1.7 g)was obtained in the form of a white solid by the same method as that of(Example 3.18) <Step 6> or a method equivalent thereto.

<Step 4> Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (17 mg) obtained in (Example 5.1) <Step 3> and the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(21 mg) obtained in (Example 1.4) <Step 2>, the title compound (14 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 2.3) or a method equivalent thereto.

Example 5.2 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid

Using 4-fluorobenzaldehyde (1.82 g), the title compound (1.93 g) wasobtained in the form of an orange solid by the same method as that of(Example 3.18) <Step 4> or a method equivalent thereto.

<Step 2> Synthesis of sodium2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Using a methanol (194 ml) solution of the2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid (1 g) obtained in (Example 5.2) <Step 1>, a crude product (1.96 g)containing the title compound was obtained in the form of a brown solidby the same method as that of (Example 5.1) <Step 1> or a methodequivalent thereto.

<Step 3> Synthesis of2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid

Concentrated hydrochloric acid (0.16 ml) was added to an aqueoussolution (2 ml) of the sodium2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate(530 mg) obtained in (Example 5.2) <Step 2>, and the obtained mixturewas then stirred for 15 minutes. Thereafter, the precipitated solid wascollected by filtration, so as to obtain the title compound (196 mg) inthe form of a whitish brown solid.

<Step 4> Synthesis of tert-butyl(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

Using the2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid (160 mg) obtained in (Example 5.2) <Step 3>, the title compound(154 mg) was obtained in the form of a light yellow solid by the samemethod as that of (Example 2.7) <Step 4> or a method equivalent thereto.

<Step 5> Synthesis of(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride

Using the tert-butyl(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate(150 mg) obtained in (Example 5.2) <Step 4>, a crude product (155 mg)containing the title compound was obtained in the form of a light yellowsolid by the same method as that of (Example 2.7) <Step 6> or a methodequivalent thereto.

<Step 6> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(4-(difluoromethyl)thiazole)-1methyl-1H-pyrazole-5-carboxylic acid (20 mg) obtained in (Example 3.12)<Step 1> and the(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (27 mg) obtained in (Example 5.2) <Step 5>, the titlecompound (29 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 1.1) <Step 4> or a method equivalentthereto.

Example 5.3 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(8 mg) obtained in (Example 5.2) <Step 6> and N-chlorosuccinimide (14mg), the title compound (5.7 mg) was obtained in the form of a colorlesssolid by the same method as that of (Example 1.4) <Step 1> or a methodequivalent thereto.

Example 5.4 Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-4,5-dimethylthiazole (274 mg), the title compound (170 mg)was obtained in the form of a white solid by the same method as that of(Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (30 mg)obtained in (Example 5.4) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-(1,2,4)triazolo(1,5-a)pyridin-7-aminehydrochloride (20 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (21 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 2.3) or a method equivalent thereto.

Example 5.5 Synthesis of4-(4-(difluoromethyl)-5-vinylthylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4-(difluoromethyl)-5-vinylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Potassium trifluorovinylborate (172 mg),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (31 mg),and triethylamine (59.4 μl) were added to an ethanol (2.1 ml) solutionof the methyl4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(150 mg) obtained in (Example 1.4) <Step 1>, and the obtained mixturewas then stirred in a nitrogen atmosphere at 100° C. for 17 hours.Thereafter, potassium trifluoro(vinyl)borate (342 mg),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (62 mg),and triethylamine (59.4 μl) were added to the reaction solution, and theobtained mixture was stirred again in a nitrogen atmosphere at 100° C.for 2 hours 40 minutes. Thereafter, ethyl acetate (100 ml) and asaturated saline (50 ml) were added to the reaction solution. An organiclayer was extracted, and was then dried over anhydrous sodium sulfate.The solvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (silicagel: eluent; heptane:ethyl acetate=95:5-50:50), so as to obtain thetitle compound (74 mg) in the form of a colorless solid.

<Step 2> Synthesis of4-(4-(difluoromethyl)-5-vinylthylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)-5-vinylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(21 mg) obtained in (Example 5.5) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (15 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (15 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 2.3) or a method equivalent thereto.

Example 5.6 Synthesis of4-(4-(difluoromethyl)-5-ethylthylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(4-(difluoromethyl)-5-ethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl4-(4-(difluoromethyl)-5-vinylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(50 mg) obtained in (Example 5.5) <Step 1>, the title compound (43 mg)was obtained in the form of a light yellow solid by the same method asthat of (Example 5.1) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-(difluoromethyl)-5-ethylthylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)-5-ethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(22 mg) obtained in (Example 5.6) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (17 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (22 mg) was obtained in the form of a light brown solid by thesame method as that of (Example 2.3) or a method equivalent thereto.

Example 5.7 Synthesis of4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate (25 mg)obtained in (Example 1.2) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (26 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (26 mg) was obtained in a white amorphous form by the samemethod as that of (Example 2.3) or a method equivalent thereto.

<Step 2> Synthesis of4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(15 mg) obtained in (Example 5.7) <Step 1>, the title compound (18 mg)was obtained in the form of a colorless solid by the same method as thatof (Example 1.4) <Step 1> or a method equivalent thereto.

Example 5.8 Synthesis of4-(5-cyclopropyl-4-(difluoromethyl)thylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Cyclopropylboronic acid (61 mg), palladium acetate (11 mg), phosphoricacid potassium salts (203 mg), water (0.53 ml), andtricyclohexylphosphine (27 mg) were added to a toluene (6 ml) solutionof the methyl4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(84 mg) obtained in (Example 1.4) <Step 1>, and the obtained mixture wasthen stirred in a nitrogen atmosphere at 100° C. for 1.5 hours.Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogencarbonate aqueous solution (30 ml) were added to the reaction solution.After extraction of organic layers, water layers were extracted withethyl acetate (50 ml). The organic layers were combined. The combinedorganic layer was washed with a saturated saline, and was then driedover anhydrous sodium sulfate. The solvent was distilled away underreduced pressure, and the obtained residue was then purified by silicagel column chromatography (silica gel: eluent; heptane:ethylacetate=93:7-40:60), so as to obtain the title compound (62 mg) in theform of a light brown solid.

<Step 2> Synthesis of4-(5-cyclopropyl-4-(difluoromethyl)thylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(22 mg) obtained in (Example 5.8) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (15 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (16 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 2.3) or a method equivalent thereto.

Example 5.9 Synthesis of1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-trifluoromethyl)thylthiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(25 mg) obtained in (Example 1.5) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (22 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (20 mg) was obtained in a white amorphous form by the samemethod as that of (Example 2.3) or a method equivalent thereto.

Example 5.10 Synthesis of4-(4-cyanothiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(4-cyanothiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using 2-bromothiazole-4-carbonitrile (150 mg), the title compound (59mg) was obtained in the form of a thick gray solid by the same method asthat of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-cyanothiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(4-cyanothiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(12 mg) obtained in (Example 5.10) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (13 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (11 mg) was obtained in the form of a gray solid by the samemethod as that of (Example 1.1) <Step 4> or a method equivalent thereto.

Example 5.11 Synthesis of4-(5-(2-ethoxyethyl)-4-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl 1-methyl-4(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate (100 mg) obtained in(Example 1.2) <Step 1>, the title compound (129 mg) was obtained in theform of a brown solid by the same method as that of (Example 1.4) <Step1> or a method equivalent thereto.

<Step 2> Synthesis of (E)-methyl4-(5-(2-ethoxyvinyl)-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg),palladium acetate (7.1 mg), tripotassium phosphate (67 mg),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (26 mg), and water(0.35 ml) were added to an acetonitrile (4.0 ml) solution of the methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (50mg) obtained in (Example 5.11) <Step 1>, and the obtained mixture wasthen stirred under heating in a nitrogen atmosphere for 2 hours at 90°C. Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogencarbonate aqueous solution (30 ml) were added to the reaction solution.After extraction of organic layers, water layers were extracted withethyl acetate (50 ml). The organic layers were combined. The combinedorganic layer was washed with a saturated saline, and was then driedover anhydrous sodium sulfate. The solvent was distilled away underreduced pressure, and the obtained residue was then purified by silicagel column chromatography (silica gel: eluent; heptane:ethylacetate=92:8-40:60), so as to obtain the title compound (31 mg) in theform of a yellow solid.

<Step 3> Synthesis of methyl4-(5-(2-ethoxyethyl)-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the (E)-methyl4-(5-(2-ethoxyvinyl)-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(27 mg) obtained in (Example 5.11) <Step 2>, the title compound (26 mg)was obtained in a yellow amorphous form by the same method as that of(Example 5.1) <Step 1> or a method equivalent thereto.

<Step 4> Synthesis of4-(5-(2-ethoxyethyl)-4-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(5-(2-ethoxyethyl)-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(14 mg) obtained in (Example 5.11) <Step 3> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (10 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (4.0 mg) was obtained in the form of a light yellow solid bythe same method as that of (Example 2.3) or a method equivalent thereto.

Example 5.12 Synthesis of4-(5-ethyl-1,3,4-thiadiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-ethyl-1,3,4-thiadiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 2-bromo-5-ethyl-1,3,4-thiadiazole (230 mg), the title compound (28mg) was obtained in the form of a light yellow solid by the same methodas that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-ethyl-1,3,4-thiadiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(5-ethyl-1,3,4-thiadiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (20mg) obtained in (Example 5.12) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (20 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (16 mg) was obtained in the form of a white solid by the samemethod as that of (Example 2.3) or a method equivalent thereto.

Example 5.13 Synthesis of4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-N-(2-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl1-methyl-4-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate (40 mg)obtained in (Example 2.12) <Step 1>, the title compound (51 mg) wasobtained in the form of a brown solid by the same method as that of(Example 1.4) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (25mg) obtained in (Example 5.13) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (20 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (10 mg) was obtained in a light yellow amorphous form by thesame method as that of (Example 2.3) or a method equivalent thereto.

Example 5.14 Synthesis of4-(3,6-dimethylpyrazin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(3,6-dimethylpyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (17 mg) obtained in (Example 3.14) <Step 2> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (15 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (11 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 1.1) <Step 4> or a method equivalentthereto.

Example 5.15 Synthesis of1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrazole-5-carboxylate

Using 5-bromo-3-methyl-1,2,4-thiadiazole (213 mg), the title compound(140 mg) was obtained in the form of a light yellow solid by the samemethod as that of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the methyl1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrazole-5-carboxylate(21 mg) obtained in (Example 5.15) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (20 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (10 mg) was obtained in the form of a light brown solid by thesame method as that of (Example 2.3) or a method equivalent thereto.

Example 5.16 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-((2R)-2-(methoxymethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Ethoxycarbonyl isothiocyanate (9.0 g) was added to a 1,4-dioxane (100ml) suspension of 2-aminopyridine-4-carboxylic acid methyl ester (10 g)at an internal temperature of 19° C. to 23° C. over 20 minutes. Theobtained mixture was stirred for 90 minutes at the same temperature asdescribed above, and was then concentrated under reduced pressure toobtain a crude product. The obtained crude product was added to a mixedsuspension of methanol (70 ml) and ethanol (70 ml) containinghydroxyamine hydrochloride (22.8 g) and diisopropylethylamine (34 ml),and thereafter, the reaction solution was stirred at room temperaturefor 67 hours, at 60° C. for 5 hours, and again, at room temperature for20 hours. Thereafter, the generated solid was collected, and it waswashed with ethanol (30 ml) and was then dried, so as to obtain thetitle compound (11.3 g) in the form of a white solid.

<Step 2> Synthesis of methyl2-amino-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Platinum(IV) oxide (3 g) was added to a mixed solution of methanol (200ml), methylene chloride (200 ml), and concentrated hydrochloric acid(3.9 ml) containing the methyl2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3.0 g) obtained in(Example 5.16) <Step 1>. The obtained mixture was stirred in a hydrogenatmosphere for 66 hours at room temperature. Thereafter, the reactionsolution was filtered with Celite, and was then washed with methanol (80ml). The filtrate was combined with the washing solution, and the thusmixed solution was then concentrated under reduced pressure. Theobtained residue was subjected to azeotropy with methanol (20 ml) fourtimes, so as to obtain the title compound (3.3 g) in the form of a lightbrown solid.

<Step 3> Synthesis of methyl2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

Tert-butyl nitrite (2.3 ml) was added to an acetonitrile (80 ml)suspension of copper(II) bromide (4.2 g), and the obtained mixture wasthen heated at 85° C. Thereafter, the methyl2-amino-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate(2.4 g) obtained in (Example 5.16) <Step 2> was added to the reactionsolution over 30 minutes, and the obtained mixture was then heated atthe same temperature as described above for 2 hours 30 minutes.Thereafter, the reaction solution was cooled to room temperature, andethyl acetate (150 ml) and water (150 ml) were then added thereto. Themixed solution was filtered with Celite, and organic layers were thenseparated. After extraction of water layers with ethyl acetate, organiclayers were combined, and were then dried over anhydrous sodium sulfate.The solvent was distilled away under reduced pressure, so that a crudeproduct of the title compound (2.7 g) was obtained in the form of abrown solid.

<Step 4> Synthesis of2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid

A 2 N sodium hydroxide aqueous solution (6.9 ml) was added to a mixedsolution of methanol (20 ml) and water (10 ml) containing the methyl2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate(2.4 g) obtained in (Example 5.16) <Step 3>. The obtained mixture wasstirred for 1 hour 30 minutes. Thereafter, methanol was distilled awayunder reduced pressure, and the obtained aqueous solution was thenwashed with ethyl acetate (2 ml). Insoluble substances were removed byfiltration. The filtrate was adjusted to pH 1 with concentratedhydrochloric acid, and was then extracted with a mixed solution (50 ml)of 20% isopropanol and methylene chloride five times. The organic layerwas dried over anhydrous sodium sulfate, and the solvent was thendistilled away under reduced pressure, so as to obtain a crude product(1.87 g) of the title compound in the form of a yellow solid.

<Step 5> Synthesis of tert-butyl(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-carbamate

Using the2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylicacid (1.8 g) obtained in (Example 5.16) <Step 4>, the title compound(2.0 g) was obtained in a white amorphous form by the same method asthat of (Example 3.15) <Step 4> or a method equivalent thereto.

<Step 6> Synthesis of2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride

Using the tert-butyl(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-carbamate(500 mg) obtained in (Example 5.16) <Step 5>, a crude product (420 mg)containing the title compound was obtained in the form of a white solidby the same method as that of (Example 3.15) <Step 5> or a methodequivalent thereto.

<Step 7> Synthesis ofN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazole)-1-methyl-1H-pyrazole-5-carboxylic acid(50 mg) obtained in (Example 3.12) <Step 1> and the2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (49 mg) obtained in (Example 5.16) <Step 6>, the titlecompound (81 mg) was obtained in the form of a white solid by the samemethod as that of (Example 1.1) <Step 4> or a method equivalent thereto.

<Step 8> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-((2R)-2-(methoxymethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

TheN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(20 mg) obtained in (Example 5.16) <Step 7> and(R)-2-(methoxymethyl)pyrrolidine (0.5 ml) were heated at 150° C. for 4days. Thereafter, ethyl acetate (50 ml) and a saturated saline (20 ml)were added to the reaction solution, and an organic layer was thenextracted. The obtained organic layer was dried over sodium sulfate. Thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by preparative thin-layer chromatography(silica gel: eluent; ethyl acetate), so as to obtain the title compound(2.1 mg) in a yellow amorphous form.

The compounds of (Example 5.17) to (Example 5.27) were synthesized usingthe 2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride obtained in (Example 5.1) <Step 3> and the correspondingcarboxylic acid or the sodium salts thereof by the same method as thatof (Example 1.1) <Step 4> or a method equivalent thereto.

Example 5.174-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.181-methyl-4-(4-methylthiazol-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.191-methyl-4-(6-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.201-methyl-4-(4-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.211-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-5-carboxamideExample 5.221-methyl-4-(3-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.234-(4-fluoropyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.244-(5-fluoropyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.254-(4-methoxypyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.261-methyl-4-(5-methylpyridin-2-yl)-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.274-(3-cyanopyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamideExample 5.28 Synthesis of4-(2,5-dimethylthiazol-4-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the after-mentioned4-(2,5-dimethylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (12mg), which will be obtained in (Example 5.39) <Step 1>, and the2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (14 mg) obtained in (Example 5.2) <Step 5>, the titlecompound (7.8 mg) was obtained in a yellow amorphous form by the samemethod as that of (Example 1.1) <Step 4> or a method equivalent thereto.

Example 5.29 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(56 mg) obtained in (Example 5.17) and N-chlorosuccinimide (99 mg), thetitle compound (40 mg) was obtained in the form of a colorless solid bythe same method as that of (Example 1.4) <Step 1> or a method equivalentthereto.

Example 5.30 Synthesis of4-(5-acetyl-2-methylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

An N,N-dimethylformamide (1 ml) solution of the4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(40 mg) obtained in (Example 5.13) <Step 2>,tributyl(1-ethoxyvinyl)stannane (58 mg), and1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (5.9 mg)was stirred in microwave at 100° C. for 40 minutes. Thereafter, 1 Nhydrochloric acid (0.3 ml) was added to the reaction solution, and theobtained mixture was then stirred for 1 hour. Thereafter, ethyl acetate(50 ml) and a saturated sodium hydrogen carbonate aqueous solution (20ml) were added to the reaction solution. The organic layer was washedwith water (20 ml) twice, and was then dried over sodium sulfate. Thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by silica gel column chromatography (silicagel: eluent; heptane:ethyl acetate=50:50-0:100), so as to obtain thetitle compound (18 mg) in a light yellow amorphous form.

Example 5.31 Synthesis of4-(5-(1-hydroxyethyl)-2-methylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Methylmagnesium bromide (0.17 ml, a 3 M diethyl ether solution) wasadded to a tetrahydrofuran (2 ml) solution of cerium(III) chloride (128mg) in a dry ice-acetone bath, and the obtained mixture was then stirredfor 30 minutes. Thereafter, the reaction solution was warmed in the icecold. A tetrahydrofuran solution of the4-(5-acetyl-2-methylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide(12 mg) obtained in (Example 5.30) was added to the reaction solution,and the obtained mixture was then warmed to room temperature. Theobtained mixture was stirred at room temperature for 1 hour, and then at40° C. for 2 hours. Thereafter, water (10 ml) was added to the reactionsolution, and the mixed solution was extracted with ethyl acetate (30ml) and was then dried over sodium sulfate. The solvent was distilledaway under reduced pressure, and sodium borohydride (0.98 mg) was thenadded to a methanol (1 ml) solution of the obtained residue, followed bystirring the mixture for 1 hour. Thereafter, water (20 ml) and ethylacetate (50 ml) were added to the reaction solution. The organic layerwas extracted, and was then dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure, and the obtainedresidue was then purified by preparative thin-layer chromatography(silica gel: eluent; ethyl acetate:methanol=95:5), so as to obtain thetitle compound (1.3 mg) in a light yellow amorphous form.

Example 5.32 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(2-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(20 mg) obtained in (Example 5.16) <Step 7> and (2-fluorophenyl)boronicacid (6.7 mg), the title compound (13 mg) was obtained in a light yellowamorphous form by the same method as that of (Example 3.15) <Step 7> ora method equivalent thereto.

Example 5.33 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride

Using 3-fluorobenzaldehyde, the title compound was obtained by applyingthe same methods as those of (Example 3.18) <Step 4>, (Example 5.1)<Step 1>, (Example 2.7) <Step 4>, and (Example 2.7) <Step 6>,successively, or methods equivalent thereto.

<Step 2> Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-aminehydrochloride (27 mg) obtained in (Example 5.33) <Step 1> and the4-(4-difluoromethyl)thiazol-2-yl)-1 methyl-1H-pyrazole-5-carboxylic acid(20 mg) obtained in (Example 3.12) <Step 1>, the title compound (28 mg)was obtained in the form of a light brown solid by the same method asthat of (Example 1.1) <Step 4> or a method equivalent thereto.

Example 5.34 Synthesis of4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(20 mg) obtained in (Example 5.16) <Step 7> and (2-methoxyphenyl)boronicacid (7.3 mg), the title compound (16 mg) was obtained in a whiteamorphous form by the same method as that of (Example 3.15) <Step 7> ora method equivalent thereto.

Example 5.35 Synthesis of4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the methyl4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(20 mg) obtained in (Example 5.8) <Step 1> and the(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (14 mg) obtained in (Example 5.2) <Step 5>, the titlecompound (10 mg) was obtained in the form of a light yellow solid by thesame method as that of (Example 1.3) <Step 2> or a method equivalentthereto.

Example 5.36 Synthesis of4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the methyl4-(4-(difluoromethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(21 mg) obtained in (Example 1.4) <Step 2> and the2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (18 mg) obtained in (Example 5.2) <Step 5>, the titlecompound (10 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 1.3) <Step 2> or a method equivalentthereto.

Example 5.37 Synthesis of4-(5-chloro-4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the4-(4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(10 mg) obtained in (Example 5.33) and N-chlorosuccinimide (17 mg), thetitle compound (7.1 mg) was obtained in the form of a colorless solid bythe same method as that of (Example 1.4) <Step 1> or a method equivalentthereto.

Example 5.38 Synthesis of4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl1-methyl-4-(4-methylthiazol-2-yl)-1H-pyrazole-5-carboxylate (100 mg)obtained in (Example 1.2) <Step 1>, the title compound (129 mg) wasobtained in the form of a brown solid by the same method as that of(Example 1.4) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid

Using the methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (25mg) obtained in (Example 5.38) <Step 1>, the title compound (20 mg) wasobtained in the form of a yellow solid by the same method as that of(Example 5.8) <Step 1> or a method equivalent thereto.

<Step 3> Synthesis of4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (20 mg) obtained in (Example 5.38) <Step 2> and a free form (16 mg)of the 2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride obtained in (Example 5.1) <Step 3>, the title compound(9.7 mg) was obtained in the form of a white solid by the same method asthat of (Example 1.1) <Step 4> or a method equivalent thereto.

Example 5.39 Synthesis of4-(2,5-dimethylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(2,5-dimethylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using 4-bromo-2,5-dimethylthiazole (61 mg), the title compound (28 mg)was obtained in the form of a light brown solid by the same methods asthose of (Example 1.1) <Step 2> and (Example 1.1) <Step 3>, or methodsequivalent thereto.

<Step 2> Synthesis of4-(2,5-dimethylthiazol-4-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(2,5-dimethylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (13 mg) obtained in (Example 5.39) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (14 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (11 mg) was obtained in a light yellow amorphous form by thesame method as that of (Example 1.1) <Step 4> or a method equivalentthereto.

Example 5.40 Synthesis of4-(6-cyanopyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(6-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using 6-bromopicolinonitrile (0.73 g) and4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (1 g), the title compound(4.7 mg) was obtained in the form of a colorless solid by the samemethod as that of (Example 3.22) <Step 1> or a method equivalentthereto.

<Step 2> Synthesis of4-(6-cyanopyridin-2-yl)-1-methyl-N-(2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using the 4-(6-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(15 mg) obtained in (Example 5.40) <Step 1> and the2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (20 mg) obtained in (Example 5.1) <Step 3>, the titlecompound (1.8 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 1.1) <Step 4> or a method equivalentthereto.

Example 5.41 Synthesis of4-(4-cyanothiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(4-cyanothiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using 2-bromothiazole-4-carbonitrile (150 mg), the title compound (59mg) was obtained in the form of a thick gray solid by the same method asthat of (Example 1.1) <Step 2> or a method equivalent thereto.

<Step 2> Synthesis of4-(4-cyanothiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(4-cyanothiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(13 mg) obtained in (Example 5.41) <Step 1> and the(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (15 mg) obtained in (Example 5.2) <Step 5>, the titlecompound (7.6 mg) was obtained in the form of a gray solid by the samemethod as that of (Example 1.1) <Step 4> or a method equivalent thereto.

Example 5.42 Synthesis of4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (23 mg) obtained in (Example 5.33) <Step 1> and the methyl4-(5-cyclopropyl-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylateobtained in (Example 5.8) <Step 1>, the title compound (16 mg) wasobtained in the form of a gray solid by the same method as that of(Example 1.3) <Step 2> or a method equivalent thereto.

Example 5.43 Synthesis of4-(5-cyclopropyl-4-methylthiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (20mg) obtained in (Example 5.11) <Step 1>, the title compound (11 mg) wasobtained in the form of an orange solid by the same method as that of(Example 5.8) <Step 1> or a method equivalent thereto.

<Step 2> Synthesis of4-(5-cyclopropyl-4-methylthiazol-2-yl)-N-(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the methyl4-(5-cyclopropyl-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(11 mg) obtained in (Example 5.43) <Step 1> and the(2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (10 mg) obtained in (Example 5.2) <Step 5>, the titlecompound (9.6 mg) was obtained in the form of a colorless solid by thesame method as that of (Example 1.3) <Step 2> or a method equivalentthereto.

Example 5.44 Synthesis of4-(5-acetyl-2-methylthiazol-4-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide<Step 1> Synthesis of methyl4-(5-acetyl-2-methylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using the methyl4-(5-bromo-2-methylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (25mg) obtained in (Example 5.13) <Step 1>, the title compound (15 mg) wasobtained in a light yellow amorphous form by the same method as that of(Example 5.30) or a method equivalent thereto.

<Step 2> Synthesis of4-(5-acetyl-2-methylthiazol-4-yl)-N-(2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the methyl4-(5-acetyl-2-methylthiazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (14mg) obtained in (Example 5.44) <Step 1> and the2-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (13 mg) obtained in (Example 5.33) <Step 1>, the titlecompound (11 mg) was obtained in a white amorphous form by the samemethod as that of (Example 1.3) <Step 2> or a method equivalent thereto.

Example 5.45 Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

Using the methyl4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (180 mg)obtained in (Example 2.2) <Step 1>, the title compound (137 mg) wasobtained in the form of a whitish brown solid by the same method as thatof (Example 1.1) <Step 3> or a method equivalent thereto.

<Step 2> Synthesis ofN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using the 4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (14 mg) obtained in (Example 5.45) <Step 1> and the2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (15 mg) obtained in (Example 5.16) <Step 6>, the titlecompound (16 mg) was obtained in a white amorphous form by the samemethod as that of (Example 1.1) <Step 4> or a method equivalent thereto.

<Step 3> Synthesis of4-(4,5-dimethylthiazol-2-yl)-1-methyl-N-(2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4,5-dimethylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide(8 mg) obtained in (Example 5.45) <Step 2> and pyrrolidine (0.5 ml), thetitle compound (2 mg) was obtained in a light yellow amorphous form bythe same method as that of (Example 4.1) or a method equivalent thereto.

Example 5.46 Synthesis of1-methyl-N-(2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis ofN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using the1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid (16 mg) obtained in (Example 4.10) <Step 1> and the2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (15 mg) obtained in (Example 5.16) <Step 6>, the titlecompound (18 mg) was obtained in the form of a whitish brown solid bythe same method as that of (Example 1.1) <Step 4> or a method equivalentthereto.

<Step 2> Synthesis of1-methyl-N-(2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(16 mg) obtained in (Example 5.46) <Step 1> and pyrrolidine (0.5 ml),the title compound (7.8 mg) was obtained in a light yellow amorphousform by the same method as that of (Example 4.1) or a method equivalentthereto.

Example 5.47 Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-N-(2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide<Step 1> Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carbonyl chloride

Oxalyl chloride (0.85 ml) was added to a mixed solution of methylenechloride (5 ml) and N,N-dimethylformamide (5 μl) containing the1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid (210 mg)obtained in (Example 3.3) <Step 1>, and the obtained mixture was thenstirred for 2 hours. Thereafter, the reaction solution was concentratedunder reduced pressure to obtain a crude product (230 mg) of the titlecompound in the form of an orange solid.

<Step 2> Synthesis ofN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide

The 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-aminehydrochloride (38 mg) obtained in (Example 5.16) <Step 6> was added at0° C. to a methylene chloride (1 ml) solution of the1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (35mg) obtained in (Example 5.47) <Step 1> and triethylamine (0.06 ml). Theobtained mixture was stirred for 30 minutes. Thereafter, a saturatedsodium hydrogen carbonate aqueous solution (2 ml) was added to thereaction solution, and the mixed solution was then purified by LC/MS, soas to obtain the title compound (29 mg) in the form of a white solid.

<Step 3> Synthesis of1-methyl-4-(6-methylpyridin-2-yl)-N-(2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide

Using theN-(2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxamide(13 mg) obtained in (Example 5.47) <Step 2> and pyrrolidine (0.2 ml),the title compound (4.4 mg) was obtained in a white amorphous form bythe same method as that of (Example 4.1) or a method equivalent thereto.

Specific embodiments disclosed in the present specification are intendedto illustrate several embodiments of the present invention. Accordingly,the present invention described and claimed in the present specificationis not limited to the scope of such embodiments. It is intended that anygiven equivalent embodiments are included in the scope of the presentinvention. As a matter of fact, from the aforementioned descriptions, aperson skilled in the art could understand that the present inventionincludes various modifications, as well as those described in thepresent specification. It is intended that such modifications are alsoincluded in the scope of the claims attached herewith.

The structures of the final compounds synthesized in the above described(Example 1.1) to (Example 5.47) will be shown in the following drawings(Structural Formula 1 to Structural Formula 10). The NMR data (Table 4to Table 12) and LC/MS data (Table 13 to Table 16) of the finalcompounds described in these Examples will also be shown in thefollowing tables.

Moreover, the structures of the intermediate compounds synthesized inindividual Examples will be shown in the following drawings (StructuralFormula 11 to Structural Formula 19). The NMR data (Table 17 to Table20) and LC/MS data (Table 21 to Table 24) of the intermediate compoundswill also be shown in the following tables.

It is to be noted that, with regard to the intermediate compounds, thecompound obtained in (Example 1.1) <Step 1>, for example, is indicatedas (Example 1.1-1).

TABLE 4 Example NMR data (δ: ppm) 1.1 ¹H-NMR (CDCl₃) δ: 8.66 (1H, s),8.11 (1H, d, J = 7 Hz), 7.98-7.93 (2H, m), 7.86 (1H, s), 7.84-7.72 (2H,m), 7.81 (1H, s), 7.68 (1H, dd, J = 8.2 Hz), 7.62 (1H, d, J = 8 Hz),7.48-7.42 (2H, m), 7.35 (1H, t, J = 7 Hz), 7.28-7.23 (1H, m), 4.36 (3H,s), 2.45 (3H, s). 1.2 ¹H-NMR (CDCl₃) δ: 13.80 (1H, brs), 8.12 (1H, d, J= 7 Hz), 8.04 (1H, s), 7.97-7.93 (2H, m), 7.88 (1H, s), 7.81 (1H, s),7.45 (2H, t, J = 8 Hz), 7.36 (1H, d, J = 8 Hz), 7.27-7.23 (1H, m), 6.94(1H, d, J = 1 Hz), 4.37 (3H, s), 2.66 (3H, s). 1.3* ¹H-NMR (CDCl₃) δ:11.84 (1H, s), 8.64 (1H, d, J = 8 Hz), 8.48 (1H, s), 8.23 (1H, s), 8.17(1H, s), 8.13 (1H, t, J = 2 Hz), 7.98-7.90 (2H, m), 7.60-7.45 (2H, m),7.45-7.34 (1H, m), 7.23 (1H, d, J = 8 Hz), 7.12 (1H, t, J = 54 Hz) 4.09(3H, s). 1.6* ¹H-NMR (CDCl₃) δ: 11.99 (1H, s), 8.17-7.83 (7H, m), 7.68(2H, d, J = 8 Hz), 7.42 (2H, t, J = 7 Hz), 7.32 (1H, t, J = 7 Hz), 7.15(1H, dd, J = 7.1 Hz), 4.3 (3H, s). 2.1 ¹H-NMR (CDCl₃) δ: 11.74 (1H, d, J= 6 Hz), 7.82 (1H, s), 7.76-7.72 (2H, m), 7.39-7.33 (2H, m), 7.25-7.21(1H, m), 7.12 (1H, s), 6.82 (1H, d, J = 1 Hz), 4.64-4.54 (1H, m), 4.32(3H, s), 4.20-4.05 (2H, m), 3.47 (1H, dd, J = 16.5 Hz), 3.08 (1H, dd, J= 16.8 Hz), 2.80 (3H, s), 2.50- 2.41 (1H, m), 2.37 (3H, d, J = 1 Hz),2.23-2.12 (1H, m).

TABLE 5 Example NMR data (δ: ppm) 2.7* ¹H-NMR (CDCl₃) δ: 10.93 (1H, d, J= 6 Hz), 7.76 (1H, S), 7.72-7.58 (1H, m), 7.58-7.38 (2H, m), 7.12 (1H,s), 6.95-6.82 (1H, m), 6.68 (1H, t, J = 54 Hz), 4.63-4.20 (1H,m), 4.30(3H, s), 4.21-3.95 (2H, m), 3.50-3.23 (1H, m), 3.07-2.84 (1H, m), 2.58(3H,s), 2.42-2.30 (1H, m), 2.30-2.00 (1H, m). 2.9 ¹H-NMR (CDCl₃) δ:11.56 (1H, d, J = 7 Hz), 7.75-7.71 (3H, m), 7.68 (1H, t, J = 8 Hz), 7.42(1H, d, J = 8 Hz), 7.39-7.33 (2H, m), 7.24- 7.20 (1H, m), 7.11 (1H, s),7.08 (1H, d, J = 8 Hz), 4.65-4.54 (1H, m), 4.29 (3H, s), 4.15-4.05 (2H,m), 3.48-3.40 (1H, m), 2.97 (1H, dd, J = 16, 10 Hz), 2.53 (3H, s),2.48-2.39 (1H, m), 2.18-2.05 (1H, m). 2.11* ¹H-NMR (CDCl₃) δ: 12.23 (1H,d, J = 3 Hz), 7.82-7.73 (4H, m), 7.51-7.41 (3H, m),7.29 (1H, d, J = 9Hz), 7.18 (1H, s), 6.69 (1H, d, J = 9.0 Hz), 4.59-4.58 (1H m), 4.29 (3H,s), 4.29-4.20 (2H, m), 3.91 (3H, s), 3.79 (1H, dd, J = 18.6 Hz), 3.52(1H, dd, J = 18 Hz, 9 Hz), 2.57-2.51 (1H, m), 2.40-2.35 (1H, m). 2.13¹H-NMR (CDCl₃) δ: 11.16 (m, d, J = 6 Hz), 8.79 (1H, s), 8.44 (1H, s),7.88 (1H, s), 7.70 (2H, d, J = 8 Hz), 7.50-7.43 (3H, m), 7.21 (1H, s),4.65-4.54 (1H, m), 4.37-4.21 (2H, m), 4.31 (3H, s), 3.88 (1H, dd, J =18.5 Hz), 3.30 (1H, dd, J = 18.10 Hz), 2.72-2.60 (1H, m), 2.62 (3H, s),2.40-2.15 (1H, m).

TABLE 6 Example NMR data (δ: ppm) 2.15 ¹H-NMR (CDCl₃) δ: 11.87 (1H, d, J= 7 Hz), 7.81-7.76 (2H, m), 7.72 (1H, s), 7.42-7.36 (2H, m), 7.29-7.23(1H, m), 7.14 (1H, s), 7.02-6.98 (1H, m), 4.72-4.62 (1H, m), 4.31 (3H,s), 4.15-4.02 (2H, m), 3.33 (1H, dd, J = 17.5 Hz), 3.17 (1H, dd, J =17.5 Hz), 2.39-2.28 (2H, m), 2.32 (3H, s). 2.19 ¹H-NMR (CDCl₃) δ: 10.63(1H, d, J = 6 Hz), 7.90-7.86 (1H, m), 7.81-7.74 (3H, m),7.43-7.35 (2H,m), 7.25-7.18 (1H, m), 4.58-4.43 (1H, m), 4.39-4.26 (3H, m), 4.20-4.08(1H, m), 4.00-3.88 (1H, m), 3.41-3.31 (1H, m), 3.00-2.74 (1H, m),2.51-2.41 (1H, m), 2.17-2.00 (1H, m). 3.1 ¹H-NMR (CDCl₃) δ: 13.28 (1H,s), 9.04 (1H, d, J = 7 Hz), 8.60-8.53 (2H, m), 8.27-8.23 (2H, m),7.74-7.69 (2H, m), 7.54-7.44 (3H, m), 7.35-7.25 (1H, m), 4.31 (3H, s),2.51 (3H, s). 3.3 ¹H-NMR (DMSO-d₆) δ: 13.14 (1H, s), 9.30 (1H, d, J = 5Hz), 8.37 (1H, d, J = 7 Hz), 8.17 (2H, dd, J = 8.2 Hz), 8.07 (1H, s),7.81 (1H, t, J = 8 Hz), 7.67 (1H, d, J = 8 Hz), 7.54-7.45 (3H, m), 7.23(1H, d, J = 8 Hz), 4.16 (3H, s), 2.51-2.45 (3H, m). 3.4 ¹H-NMR (DMSO-d₆)δ: 9.24-9.15 (1H, m), 8.68-8.60 (1H, m), 8.22-8.10 (3H, m), 8.00-7.92(1H, m), 7.67-7.58 (1H, m), 7.58-7.41 (3H, m), 7.33- 7.23 (1H, m), 4.21(3H, s).

TABLE 7 Example NMR data (δ: ppm) 3.6 ¹H-NMR (CDCl₃) δ: 12.32 (1H, s),8.86-8.80 (1H, m), 8.65-8.60 (1H, m), 8.30-8.22 (2H, m), 7.96-7.90 (1H,m), 7.85-7.80 (1H, m), 7.54-7.43 (3H, m), 4.37 (3H, s). 3.9 ¹H-NMR(CDCl₃) δ: 12.67 (1H, s), 8.82 (1H, s), 8.76 (1H, d, J = 7 Hz), 8.63(1H, d, J = 5 Hz), 8.48 (1H, s), 8.28-8.23 (2H, m), 7.92 (1H, s),7.54-7.46 (3H, m), 4.35 (3H, s), 2.66-2.64 (3H, s). 3.12 ¹H-NMR (CDCl₃)δ: 12.85 (1H, s), 8.99 (1H, d, J = 6 Hz), 8.64 (1H, d, J = 6 Hz),8.28-8.26 (2H, m), 7.94 (1H, s), 7.72 (1H, s), 7.53-7.50 (3H, m), 6.88(1H, t, J = 39 Hz), 4.39 (3H, s). 3.13 ¹H-NMR (CDCl₃) δ: 13.08 (1H, s),9.08 (1H, d, J = 6 Hz), 8.92-8.91 (1H, m), 8.60 (1H, d, J = 6 Hz),8.27-8.20 (4H, m), 7.51-7.48 (4H, m), 4.37 (3H, s). 3.14 ¹H-NMR (CDCl₃)δ: 11.13 (1H, s), 8.82-8.80 (1H, m), 8.57-8.56 (1H, m), 8.42 (1H, s),8.26-8.24 (2H, m), 7.67 (1H, s), 7.50-7.49 (3H, m), 4.30 (3H, s), 2.66(3H, s), 2.63 (3H, s). 3.19* ¹H-NMR (DMSO-d₆) δ: 11.76 (1H, br-s), 8.63(1H, d, J = 1 Hz), 8.16 (1H, s), 8.14-8.11 (1H, m), 7.89 (1H, d, J = 2Hz), 7.15 (1H, dd, J = 7.2 Hz), 7.12 (1H, t, J = 54 Hz), 4.08 (3H, s),4.00-3.92 (2H, m), 3.73-3.60 (2H, m), 2.63-2.53 (2H, m), 1.16 (6H, d, J= 6 Hz).

TABLE 8 Example NMR data (δ: ppm) 3.22 ¹H-NMR (CDCl₃) δ: 11.72 (1H, s),8.78 (1H, d, J = 8 Hz), 8.63 (1H, s), 8.59 (1H, d, J = 8 Hz), 8.27-8.24(2H, m), 7.70 (1H, s), 7.51-7.49 (3H, m), 4.31 (3H, s), 2.78 (3H, s),2.42 (3H, s). 3.25 ¹H-NMR (CDCl₃) δ: 13.39 (1H, s), 8.75-8.64 (3H, m),8.28-8.26 (2H, m), 7.96 (1H, s), 7.52-7.47 (4H, m), 4.36 (3H, s), 2.79(3H, s). 3.29* ¹H-NMR (CDCl₃) δ: 12.82 (1H, br), 9.20 (1H, d, J = 2 Hz),9.07 (1H, d, J = 8 Hz), 8.90 (1H, s), 8.62 (1H, d, J = 5 Hz), 8.38-8.28(2H, m), 8.23 (1H, s), 7.54-7.46 (3H, m), 4.34 (3H, s). 3.31 ¹H-NMR(CDCl₃) δ: 13.25 (1H, s), 9.05-9.03 (1H, m), 8.76 (1H, s), 8.57 (1H, m),8.26-8.25 (2H, m), 7.68 (1H, d, J = 4 Hz), 7.50-7.48 (3H, m), 4.31 (3H,s), 4.08 (3H, s), 2.31 (3H, s). 3.32 ¹H-NMR (CDCl₃) δ: 12.56 (1H, brs),9.03, (1H, d, J = 7.3 Hz), 8.57-8.51 (3H, m), 8.24 (2H, dd, J = 7.8 Hz,1.8 Hz), 7.77 (1H, s), 7.51-7.44 (3H, m), 4.32 (3H, s), 2.76 (3H, s).3.33 ¹H-NMR (CDCl₃) δ: 13.17 (1H, s), 9.19 (1H, s), 9.08-9.05 (1H, m),8.75-8.74 (1H, m), 8.62-8.60 (1H, m), 8.27-8.26 (2H, m), 7.82 (1H, d, J= 8 Hz), 7.51-7.49 (3H, m), 4.34 (3H, s), 2.53 (3H, s). 3.36 ¹H-NMR(CDCl₃) δ: 12.53 (1H, s), 8.74 (1H, d, J = 7 Hz), 8.63 (1H, d, J = 2Hz), 8.62 (1H, s), 8.28-8.23 (2H, m), 8.09 (1H, d, J = 5 Hz), 7.53-7.44(3H, m), 4.33 (3H, s), 2.75 (3H, s).

TABLE 9 Example NMR data (δ: ppm) 4.1* ¹H-NMR (DMSO-d₆) δ: 11.70 (1H,s), 8.62 (1H, d, J = 7 Hz), 8.15 (1H, s), 8.14-8.10 (1H, m), 7.86 (1H,d, J = 2 Hz), 7.12 (1H, t, J = 54 Hz), 7.10 (1H, dd, J = 7 Hz, J = 2Hz), 4.07 (3H, s), 4.04-3.94 (1H, m), 3.57- 3.38 (2H, m), 2.16-1.81 (3H,m), 1.70-1.61 (1H, m), 1.26 (3H, d, J = 6 Hz). 4.3* ¹H-NMR (CDCl₃) δ:11.86 (1H, s), 8.28 (1H, d, J = 7 Hz), 8.04 (1H, t, J = 8 Hz), 7.80-7.88(3H, m), 7.68 (1H, dd, J = 8.1 Hz), 7.00 (1H, dd, J = 7, 2 Hz), 4.30(3H, s), 4.10-4.20 (1H, m), 3.64-3.72 (1H, m), 3.50-3.60 (1H, m),1.90-2.21 (3H, m), 1.68-1.77 (1H, m), 1.34 (3H, d, J = 6 Hz). 4.6 ¹H-NMR(DMSO-d₆) δ: 11.16 (1H, s), 8.84 (1H, s), 8.60 (1H, d, J = 8 Hz), 8.37(1H, s), 8.23 (1H, s), 7.83 (1H, d, J = 4 Hz), 7.03 (1H, dd, J = 8.4Hz), 4.00 (3H, s), 4.00-3.97 (1H, m), 3.54-3.48 (1H, m), 3.42-3.36 (1H,m), 2.28 (3H, s), 2.11-1.99 (2H, m), 1.92-1.87 (1H, m), 1.67-1.63 (1H,m), 1.26 (3H, d, J = 8 Hz). 4.10 ¹H-NMR (CDCl₃) δ: 12.77 (1H, s), 8.36(1H, d, J = 2 Hz), 8.30 (1H, d, J = 7 Hz), 7.94 (1H, s), 7.84 (1H, s),7.46 (1H, dd, J = 7.2 Hz), 4.37 (3H, s), 4.25- 4.14 (1H, m), 3.80-3.70(1H, m), 3.64-3.52 (1H, m), 2.23-1.86 (3H, m), 1.81- 1.73 (1H, m), 1.31(3H, d, J =6 Hz)..

TABLE 10 Example NMR data (δ: ppm) 4.11 ¹H-NMR (DMSO-d₆) δ: 8.99 (1H,s), 8.05-7.99 (2H, m), 7.82-7.74 (1H, m), 7.66 (1H ,d, J = 8 Hz), 7.20(1H, d, J = 8 Hz), 4.74-4.64 (1H, m), 4.12 (3H, s), 3.76-3.54 (4H, m),2.44 (3H, s), 2.22-1.95 (2H, m). 4.13* ¹H-NMR (CDCl₃) δ: 12.35 1H, s),8.28 (1H, d, J = 7 Hz), 8.19 (H, d, J = 2 Hz), 7.92 (1H, s), 7.83 (1H,d, J = 1 Hz), 7.04 (1H, dd, J = 7.2 Hz), 5.28- 5.50 (1H, m), 4.37 (3H,s), 3.67-4.03 (4H, m), 2.00-2.48 (2H, m). 4.23* ¹H-NMR (CDCl₃) δ: 12.76(1H, s), 8.27 (1H, d, J = 6 Hz), 8.13 (1H, s), 7.83 (1H, s), 7.27-7.20(1H, m), 6.88 (1H, t, J = 54 Hz), 5.48-5.30 (1H, m), 4.36 (3H, s),4.01-3.68 (4H, m), 2.64 (3H, s), 2.40-2.11 (2H, m). 4.24* ¹H-NMR (CDCl₃)δ: 13.96 (1H, br s), 8.37 (1H, d, J = 5 Hz), 8.18 (1H, d, J = 7 Hz),7.82 (1H, s), 7.32 (1H, s), 6.98 (1H, s), 5.50-5.25 (1H, m), 4.31 (3H,s), 4.00-3.65 (4H, m), 2.52 (3H, d, J = 2 Hz), 2.41 (3H, s), 2.48-2.00(2H, m). 4.25* ¹H-NMR (DMSO-d₆) δ: 11.70 (1H, br-s), 8.60 (1H, d, J = 7Hz), 8.14 (1H, s), 8.12-8.09 (1H, m), 7.83 (1H, d, J = 2 Hz), 7.11 (1H,t, J = 54 Hz), 7.10 (1H, dd, J = 7.2Hz), 4.06 (3H, s), 3.46-3.39 (4H,m), 1.98-1.88 (4H, m).

TABLE 11 Example NMR data (δ: ppm) 4.27* ¹H-NMR(CDCl₃) δ: 12.03 (1H, s),8.28 (1H, d, J = 9 Hz), 8.03 (1H, dd, J = 10 Hz), 7.95 (1H, br),7.87-7.84 (2H, m), 7.68 (1H, d, J = 6 Hz), 7.32-7.29 (1H, m), 4.28 (3H,s), 3.71-3.49 (4H, m), 2.13-1.96 (4H, m). 4.29 ¹H-NMR (DMSO-d₆) δ: 11.17(1H, s), 8.84 (1H, s), 8.59 (1H, d, J = 8 Hz), 8.37 (1H, s), 8.23 (1H,s), 7.83 (1H, d, J = 4 Hz), 7.04 (1H, dd, J = 8.4 Hz), 4.00 (3H, s),3.45-3.41 (4H, m), 2.28 (3H, s), 1.96-1.93 (4H, m). 4.34 ¹H-NMR (CDCl₃)δ: 12.57 (1H, s), 8.30-8.25 (2H, m), 7.93 (1H, s), 7.84-7.82 (1H, m),7.29-7.24 (1H, m), 4.37 (3H, s), 3.64-3.57 (4H, m), 2.07-2.01 (4H, m).5.2 ¹H-NMR (DMSO-d₆) δ: 9.68 (1H, d, J = 8 Hz), 8.13-7.92 (4H, m),7.32-7.23 (2H, m), 7.12 (1H, t, J = 39 Hz), 4.62-4.52 (1H, m), 4.27-4.24(2H, m), 3.96 (3H, s), 3.47-3.20 (1H, m), 3.00-2.86 (1H, m), 2.33-2.14(2H, m). 5.9* ¹H-NMR (CDCl₃) δ: 10.74 (1H, d, J = 7 Hz), 8.12-8.05 (2H,m), 7.90 (1H, s), 7.79 (1H, d, J = 1), 7.48-7.38 (3H, m), 4.68-4.54 (1H,m), 4.50-4.42 (1H, m), 4.34 (3H, s), 4.36-4.24 (1H, m), 3.58-3.48 (1H,m), 3.01 (1H, dd, J = 16.10 Hz), 2.60-2.49 (1H, m), 2.32-2.16 (1H, m).

TABLE 12 Example NMR data (δ: ppm) 5.10* ¹H-NMR (DMSO-d₆) δ: 9.43 (1H,d, J = 7 Hz), 8.77 (1H, s), 8.06 (1H, s), 8.00-7.94 (2H, m), 7.48-7.35(3H, m), 4.67-4.55 (1H, m), 4.3-4.20 (2H, m), 3.92 (3H, s), 3.00- 2.88(1H, m), 2.18-2.42 (2H, m). 5.12 ¹H-NMR (CDCl₃) δ: 11.34 (1H, d, J = 6Hz), 8.12-8.07 (2H, m), 7.74 (1H, s), 7.45- 7.36 (3H, m), 4.73-4.65 (1H,m), 4.57-4.50 (1H, m), 4.42-4.33 (1H, m), 4.34 (3H, s), 3.42 (1H, dd, J= 17.5 Hz), 3.25 (1H, dd, J = 17.7 Hz), 3.07 (2H, q, J = 7 Hz),2.56-2.35 (2H, m), 1.40 (3H, t, J = 1 Hz). 5.16* ¹H-NMR (CDCl₃) δ: 10.83(1H, d, J = 6 Hz), 7.86 (1H, s), 7.62-7.58 (1H, m), 6.72 (1H, dt, J =55.2 Hz), 4.64-4.49 (1H, m), 4.32 (3H, s), 4.17-3.97 (2H, m), 3.70-3.48(4H, m), 3.42-3.21 (2H, s), 3.39 (3H, s) 3.00-2.85 (1H, m), 2.44-2.17(2H, m), 2.13- 1.83 (4H, m). Example No. with symbol *: measured at 300MHz NMR; and Example No. without symbol *: measured at 400 MHz NMR.

TABLE 13 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time(min) Example [M+H]⁺ time (min) 1.1 409 5.02 2.17 402 2.55 1.2 4155.28 2.18^(#) 456 3.82 1.3^(##) 451 0.96 2.19^(##) 491 1.04 1.4^(##) 4650.99 2.20^(##) 473 0.83 1.5^(##) 469 0.97 2.21 413 4.22 1.6 463 4.672.22^(##) 413 0.73 1.7 485 5.42 2.23^(#) 432 3.77 2.1^(##) 419 0.842.24^(#) 432 3.55 2.2^(#) 433 4.37 2.25^(#) 405 3.67 2.3^(#) 473 4.172.26^(#) 405 3.90 2.4^(##) 455 0.84 2.27^(##) 461 0.92 2.5 489 4.382.28^(##) 473 0.83 2.6 469 4.25 2.29 491 4.55 2.7^(##) 487 0.87 3.1^(#)428 1.22 2.8^(##) 491 0.87 3.2^(#) 429 1.24 2.9^(##) 413 0.66 3.3^(#)428 1.21 2.10^(##) 420 0.77 3.4^(#) 432 1.27 2.11^(#) 429 3.97 3.5^(##)428 1.31 2.12^(#) 419 3.83 3.6^(#) 488 1.25 2.13^(#) 414 3.43 3.7^(#)444 1.25 2.14^(##) 448 0.88 3.8 432 6.37 2.15^(##) 419 0.87 3.9^(##) 4291.16 2.16^(#) 414 3.65 3.10 482 5.92 Example No. without symbol: HPLC(AcOH) system; Example No. with symbol ^(#): HPLC (TFA) system; andExample No. with symbol ^(##): UPLC system. In MS-ESI (m/z), ^(*): [M −H]⁻; and ^(**): [M + Na]⁺.

TABLE 14 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 3.11^(##) 442 1.22 3.35^(##) 4431.23 3.12^(##) 470 1.24 3.36^(##) 447 1.14 3.13^(##) 439 1.17 3.37^(##)457 1.12 3.14^(##) 443 1.14 3.38^(#) 447 6.30 3.15^(##) 452 1.25 3.39429 6.05 3.16^(##) 482 1.14 3.40^(##) 475 1.26 3.17^(##) 470 1.253.41^(##) 463 1.15 3.18^(##) 430 1.33 3.42^(##) 445 1.11 3.19 489 6.003.43 429 6.28 3.20^(##) 486 1.21 3.44^(##) 443 6.17 3.21^(##) 550 1.223.45^(##) 429 1.18 3.22^(##) 443 1.13 3.46^(##) 429 1.20 3.23^(##) 4391.21 3.47^(##) 415 1.17 3.24 429 5.55 3.48^(##) 417 1.07 3.25^(##) 4291.16 3.49 444 5.02 3.26^(##) 445 1.16 3.50^(##) 457 1.14 3.27^(##) 4631.13 3.51^(##) 428 1.33 3.28 445 6.23 3.52^(##) 444 1.28 3.29^(#) 4495.83 3.53^(##) 442 1.20 3.30^(#) 443 5.72 3.54 460 6.48 3.31^(#) 4596.38 4.1 459 6.03 3.32 429 5.77 4.2^(#) 493 6.03 3.33^(##) 429 1.18 4.3471 5.65 3.34^(##) 445 1.23 4.4 417 6.15 Example No. without symbol:HPLC (AcOH) system; Example No. with symbol ^(#): HPLC (TFA) system; andExample No. with symbol ^(##): UPLC system. In MS-ESI (m/z), ^(*): [M −H]⁻; and ^(**): [M + Na]⁺.

TABLE 15 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 4.5 433 6.12 4.29 404 5.18 4.6418 5.43 4.30 403 5.95 4.7 417 5.93 4.31 403 5.72 4.8 431 6.17 4.32 4175.95 4.9 473 6.23 4.33 459 6.07 4.10 477 6.13 4.34 463 5.95 4.11^(##)490 1.18 4.35 436 1.01 4.12^(##) 463 1.10 4.36^(#) 523 5.98 4.13 4815.72 5.1^(#) 470 5.57 4.14 477 5.83 5.2^(#) 474 1.09 4.15^(##) 463 1.125.3 508 5.83 4.16 475 5.23 5.4^(#) 434 5.85 4.17 421 5.73 5.5^(#) 4825.77 4.18 437 5.65 5.6^(#) 484 5.82 4.19 422 4.93 5.7^(#) 498 1.22 4.20435 5.70 5.8^(#) 496 5.85 4.21 421 5.47 5.9 474 5.52 4.22 481 5.72 5.10431 4.98 4.23 477 5.85 5.11^(#) 492 5.90 4.24 453 5.85 5.12 435 5.124.25 445 5.83 5.13^(#) 498 5.40 4.26^(##) 479 1.16 5.14 429 4.754.27^(#) 457 5.12 5.15 421 5.23 4.28 419 5.90 5.16 493 5.12 Example No.without symbol: HPLC (AcOH) system; Example No. with symbol ^(#): HPLC(TFA) system; and Example No. with symbol ^(##): UPLC system. In MS-ESI(m/z), ^(*): [M − H]⁻; and ^(**): [M + Na]⁺.

TABLE 16 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 5.17 456 5.35 5.33 474 5.57 5.18420 5.50 5.34 486 5.08 5.19 414 5.20 5.35^(#) 514 6.00 5.20 414 5.455.36^(#) 488 5.73 5.21^(##) 468 1.07 5.37 508 5.85 5.22 414 5.025.38^(#) 460 6.12 5.23 418 5.33 5.39 434 5.25 5.24 418 5.27 5.40 4255.00 5.25 430 5.28 5.41^(#) 449 5.22 5.26 414 5.48 5.42^(#) 514 6.035.27 425 4.77 5.43^(#) 478 6.25 5.28 452 5.43 5.44 480 5.02 5.29^(##)490 1.12 5.45 427 5.48 5.30 462 4.80 5.46 467 5.25 5.31 464 4.905.47^(##) 407 0.72 5.32 474 5.20 Example No. without symbol: HPLC (AcOH)system; Example No. with symbol ^(#): HPLC (TFA) system; and Example No.with symbol ^(##): UPLC system. In MS-ESI (m/z), ^(*): [M − H]⁻; and^(**): [M + Na]⁺.

TABLE 17 Example NMR data (δ: ppm) 1.1-1^(*) ¹H-NMR (CDCl₃) δ: 7.58 (1H,s), 4.11 (3H, s), 3.88 (3H, s), 3.74 (4H, s), 1.05 (6H, s). 2.1-1^(*)¹H-NMR (DMSO-d₆) δ: 8.75 (3H, br), 8.11 (1H, s), 7.90-7.83 (2H, m),7.57-7.37 (3H, m), 4.38-4.09 (2H, m), 3.97-3.73 (1H, m), 3.68-3.52 (1H,m), 3.33-3.17 (1H, m), 2.48-2.13 (2H, m). 2.7-1^(*) ¹H-NMR (CDCl₃) δ:4.10-3.98 (1H, m), 3.83-3.74 (1H, m), 3.78 (3H, s), 3.22-2.87 (3H, m),2.43-2.35 (1H, m), 2.23-2.10 (1H, m). 2.7-2^(*) ¹H-NMR (CDCl₃) δ: 6.78(1H, s), 4.14-4.04 (1H, m), 3.97-3.87 (1H, m), 3.76 (3H, s), 3.22-3.14(1H, m), 3.07-3.03 (1H, m), 2.98-2.90 (1H, m), 2.38-2.32 (1H, m),2.21-2.12 (1H, m). 2.7-3^(*) ¹H-NMR (DMSO-d₆) δ: 7.15 (1H, s), 4.04-3.84(2H, m), 2.98-2.71 (3H, m), 2.30- 2.18 (1H, m), 2.04-1.88 (1H, m).2.7-4^(*) ¹H-NMR (CDCl₃) δ: 6.79 (1H, s), 4.58 (1H, brs), 4.18-3.90 (3H,m), 3.20 (1H, dd, J = 17,5 Hz), 2.70 (1H, dd, J = 17,8 Hz), 2.32-2.20(1H, m), 2.10-1.96 (1H, m), 1.46 (9H, s). Example No. with symbol ^(*):measured at 300 MHz NMR; and Example No. without symbol ^(*): measuredat 400 MHz NMR.

TABLE 18 Example NMR data (δ: ppm) 3.1-1 ¹H-NMR (CDCl₃) δ: 7.62 (1H, s),4.15 (3H, s), 3.89 (3H, s), 1.35 (12H, s). 4.24-1^(*) ¹H-NMR (DMSO-d₆)δ: 9.00 (1H, d, J = 6 Hz), 6.64 (1H, d, J = 8 Hz). 5.1-3^(*) ¹H-NMR(DMSO-d₆) δ: 8.70 (3H, m), 8.04-7.95 (1H, m), 7.53-7.39 (3H, m), 4.40-4.15 (2H, m), 3.90-3.75 (1H, m), 3.39 (1H, dd, J = 17,5 Hz), 3.08 (1H,dd, J = 17,9 Hz), 2.50-2.39 (1H, m), 2.48-2.20 (1H, m). 5.16-6^(*)¹H-NMR (DMSO-d₆) δ: 8.64 (3H, brs), 4.45-4.01 (2H, m), 3.85-3.65 (1H,m), 3.25 (1H, dd, J = 17,5 Hz), 3.01 (1H, dd, J = 17,9 Hz), 2.43-2.11(2H, m). 1.1-2 ¹H-NMR (CDCl₃) δ: 8.45 (1H, d, J = 2 Hz), 7.73 (1H, s),7.49 (1H, dd, J = 8,2 Hz), 7.38 (1H, d, J = 8 Hz), 4.17 (3H, s), 3.81(3H, s), 2.37 (3H, s). 1.1-3 ¹H-NMR (CDCl₃) δ: 8.28 (1H, d, J = 2 Hz),7.99 (1H, s), 7.79 (1H, dd, J = 8,2 Hz), 7.75 (1H, d, J = 8 Hz), 4.34(3H, s), 2.44 (3H, s) 1.2-1 ¹H-NMR (CDCl₃) δ: 8.02 (1H, s), 6.93 (1H, d,J = 1 Hz), 4.19 (3H, s), 3.95 (3H, s), 2.49 (3H, d, J = 1 Hz). 1.2-2¹H-NMR (CDCl₃) δ: 7.88 (1H, s), 6.91 (1H, d, J = 1 Hz), 4.33 (3H, s),2.49 (3H, d, J = 1 Hz). Example No. with symbol ^(*): measured at 300MHz NMR; and Example No. without symbol ^(*): measured at 400 MHz NMR.

TABLE 19 Example NMR data (δ: ppm) 2.9-1 ¹H-NMR (CDCl₃) δ: 7.72 (1H, s),7.57 (1H, dd, J = 7,7 Hz), 7.25 (1H, d, J = 7 Hz), 7.07 (1H, d, J = 7Hz), 4.15 (3H, s), 3.79 (3H, s), 2.57 (3H, s) 3.1-2^(*) ¹H-NMR (CDCl₃)δ: 8.45 (1H, d, J = 5 Hz), 7.58-7.51 (2H, m), 7.18 (1H, dd, J = 8,5 Hz),4.22 (3H, s), 3.65 (3H, s), 2.18 (3H, s). 3.1-3^(*) ¹H-NMR (CD₃OD) δ:8.46 (1H, d, J = 5 Hz), 8.11 (1H, d, J = 8 Hz), 7.93 (1H, s), 7.56 (1H,dd, J = 8,5 Hz), 4.23 (3H, s), 2.54 (3H, s). 3.3-1 ¹H-NMR (DMSO-d₆) δ:8.49-8.40 (1H, m), 8.14-8.05 (2H, m), 7.48-7.41 (1H, m), 4.18 (3H, s),2.59 (3H, s). 3.9-1^(*) ¹H-NMR (CDCl₃) δ: 8.56 (1H, s), 8.37 (1H, s),7.79 (1H, s), 4.21 (3H, s), 3.83 (3H, s), 2.60 (3H, s). 3.9-2 ¹H-NMR(DMSO-d₆) δ: 9.03 (1H, s), 8.56 (1H, s), 8.24 (1H, s), 4.15 (3H, s),2.55 (3H, s). 3.22-1 ¹H-NMR (CDCl₃) δ: 8.49 (1H, s), 7.57 (1H, s), 4.21(3H, s), 3.70 (3H, s), 2.71 (3H, s), 2.15 (3H, s). 3.22-2 ¹H-NMR(DMSO-d₆) δ: 8.49 (1H, s), 7.61 (1H, s), 4.07 (3H, s), 2.55 (3H, s),2.15 (3H, s). 3.25-1^(*) ¹H-NMR (CDCl₃) δ: 8.62 (1H, d, J = 5 Hz), 7.85(1H, s), 7.29 (1H, d, J = 5 Hz), 4.15 (3H, s), 3.87 (3H, s), 2.74 (3H,s). Example No. with symbol ^(*): measured at 300 MHz NMR; and ExampleNo. without symbol ^(*): measured at 400 MHz NMR.

TABLE 20 Example NMR data (δ: ppm) 3.25-2^(*) ¹H-NMR (CDCl₃) δ: 8.79(1H, d, J = 6 Hz), 8.09 (1H, s), 7.56 (1H, d, J = 6 Hz), 4.36 (3H, s),2.81 (3H, s). 3.31-1^(*) ¹H-NMR (CDCl₃) δ: 8.63 (1H, s), 7.54 (1H, s),4.21 (3H, s), 4.04 (3H, s), 3.72 (3H, s), 2.01 (3H, s). 3.31-2 ¹H-NMR(CDCl₃) δ: 8.63 (1H, s), 7.92 (1H, s), 4.31 (3H, s), 4.11 (3H, s), 2.43(3H, s). 3.36-1 ¹H-NMR (CDCl₃) δ: 8.47 (1H, d, J = 2 Hz), 7.83 (1H, d, J= 1 Hz), 4.16 (3H, s), 3.84 (3H, s), 2.73 (3H, d, J = 1 Hz) 3.36-2¹H-NMR (DMSO-d₆) δ: 8.78 (1H, d, J = 2 Hz), 7.89 (1H, d, J = 1 Hz), 4.10(3H, s), 2.63 (3H, d, J = 1 Hz) Example No. with symbol ^(*): measuredat 300 MHz NMR; and Example No. without symbol ^(*): measured at 400 MHzNMR.

TABLE 21 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 1.1-1^(##) 185^(♦) 0.672.13-1^(##) 233   0.75 1.2-1^(##) 238   0.91 2.13-2^(##) 219^($$) 0.741.3-1 274   4.57 2.14-1^(##) 267   1.14 1.4-1^(##) 352   1.112.15-1^(##) 238   0.93 1.4-2^(##) 288   1.01 2.16-1^(##) 233   0.751.5-1^(##) 292   1.05 2.16-2^(##) 241^($$) 0.77 1.6-1^(##) 286   1.002.17-1^(##) 221   0.52 1.7-1^(##) 308   1.10 2.18-1^(##) 289   1.081.7-2^(##) 316^(**) 1.02 2.18-2^(##) 275   0.97 2.2-1^(##) 252   0.952.18-3^(##) 346   0.94 2.2-2^(##) 260^($)  0.85 2.18-4^(##) 246   0.772.7-1^(##) 337   0.93 2.18-5^(##) 250   0.48 2.7-2^(##) 259   0.522.19-1^(##) 309   1.09 2.7-4^(##) 316   0.76 2.19-2^(##) 271   1.152.7-6^(##) 232   0.49 2.19-3^(##) 275   0.74 2.8-1^(#) 278   4.982.19-4^(##) 239   0.74 2.9-1^(##) 232   0.52 2.19-5^(##) 332   0.882.10-1^(##) 239   0.80 2.19-6^(##) 232   0.62 2.10-2^(##) 247^(*)  0.692.19-7^(##) 300^($$) 0.97 2.11-1 248   4.68 2.25-1^(##) 224   0.832.11-2^(##) 256^($)  0.82 2.26-1^(##) 224   0.87 2.12-1^(##) 238   0.902.27-1^(##) 280   1.15 Example No. without symbol: HPLC (AcOH) system;Example No. with symbol ^(#): HPLC (TFA) system; and Example No. withsymbol ^(##): UPLC system. In MS-ESI (m/z), *: [M − H]⁻; and ^(**): [M +Na]⁺; ^(♦): measured as [M + H]⁺ of the corresponding boronic acid;^($): measured as [M + Na]⁺ of carboxylic acid; and ^($$): measured as[M + H]⁺ of carboxylic acid.

TABLE 22 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 2.28-1^(##) 232   0.473.15-6^(##) 454   1.15 3.1-1^(##) 267   1.00 3.18-1^(##) 252   0.993.1-2^(##) 232   0.54 3.18-2^(##) 238   0.90 3.1-3^(##) 218   0.523.18-4^(##) 240   1.03 3.2-1^(#) 219   3.62 3.18-5^(##) 311   1.1163.3-1^(##) 240^(**) 0.65 3.22-1^(##) 247   0.73 3.4-1^(##) 244^($)  0.663.22-2^(##) 233   0.65 3.5-1^(##) 240^($)  0.69 3.23-1^(##) 229   0.723.6-1# 278   4.98 3.24-1^(##) 233   0.63 3.7-1^(##) 256^($)  0.723.24-2^(##) 241^(**) 0.52 3.8-1^(##) 244^($)  0.74 3.25-1^(##) 233  0.75 3.9-1 233   3.85 3.25-2^(##) 219   0.67 3.9-2^(##) 241^(**) 0.743.26-1^(##) 249   0.84 3.10-1^(##) 294^(**) 0.93 3.26-2^(##) 235   0.793.11-1^(##) 254^($)  0.75 3.27-1^(##) 267   0.91 3.12-1^(##) 260   0.853.27-2^(##) 275^(**) 0.81 3.13-1^(##) 243   0.74 3.28-1 249   4.023.13-2^(##) 229   0.67 3.28-2^(##) 257^(**) 0.84 3.14-1^(##) 247   0.783.29-1^(##) 253   0.84 3.14-2^(##) 233   0.71 3.29-2^(##) 239   0.733.15-1^(##) 193   0.65 3.30-1^(##) — — 3.15-4 313   5.30 3.30-2^(##)233   0.72 3.15-5 213   3.15 3.31-1^(##) 263   0.86 Example No. withoutsymbol: HPLC (AcOH) system; Example No. with symbol ^(#): HPLC (TFA)system; and Example No. with symbol ^(##): UPLC system. In MS-ESI (m/z),^(*): [M − H]⁻; and ^(**): [M + Na]⁺; ^($): measured as [M + Na]⁺ ofcarboxylic acid; and ^($$): measured as [M + H]⁺ of carboxylic acid.

TABLE 23 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 3.31-2^(##) 249 0.74 3.43-1^(##)233   0.76 3.32-1^(##) 233 0.74 3.43-2^(##) 241^(**) 0.78 3.32-2^(##)219 0.67 3.44-1^(##) 247   0.79 3.33-1^(##) 233 0.73 3.44-2^(##) 233  0.82 3.33-2^(#) 219 2.50 3.45-1^(##) 233   0.66 3.34-1^(##) 249 0.753.45-2^(##) 219   0.64 3.34-2^(##) 235 0.72 3.46-1^(##) 233   0.693.35-1^(##) 247 0.77 3.46-2^(##) 219   0.63 3.35-2^(##) 233 0.663.47-1^(##) 219   0.64 3.36-1^(#) 251 4.07 3.47-2^(##) 205   0.583.37-1^(##) 261 0.74 3.49-1^(##) 445   0.97 3.37-2^(#) 247 2.753.54-1^(##) 369^(**) 1.17 3.38-1^(##) 251 0.87 3.54-2^(#) 247   4.503.38-2^(##) 237 0.79 4.3-1^(##) 218   0.72 3.39-1 233 3.72 4.4-1 232  2.90 3.39-2^(#) 219 3.23 4.4-2^(##) 240   0.66 3.40-1^(##) 279 0.954.5-1 248   1.30 3.40-2^(##) 265 0.89 4.5-2^(##) 234   0.66 3.41-1^(##)267 0.90 4.8-1^(##) 246   0.59 3.41-2^(##) 253 0.80 4.8-2^(##) 232  0.72 3.42-1^(##) 249 0.93 4.9-1^(##) 296^(**) 0.93 3.42-2^(##) 235 0.844.10-1^(#) 278   4.96 Example No. without symbol: HPLC (AcOH) system;Example No. with symbol ^(#): HPLC (TFA) system; and Example No. withsymbol ^(##): UPLC system. In MS-ESI (m/z), ^(*): [M − H]⁻; and ^(**):[M + Na]⁺; ^($): measured as [M + Na]⁺ of carboxylic acid; and ^($$):measured as [M + H]⁺ of carboxylic acid.

TABLE 24 MS-ESI MS-ESI (m/z) Retention (m/z) Retention Example [M + H]⁺time (min) Example [M + H]⁺ time (min) 4.11-1^(##) 211   0.675.11-1^(##) 316   1.16 4.11-2^(##) 274   0.86 5.11-2^(##) 308   1.134.11-3^(##) 260   0.74 5.11-3^(##) 310   1.01 4.11-4^(##) 353   1.045.12-1^(##) 253   0.89 4.11-5^(##) 412^(**) 1.12 5.13-1^(##) 316   0.984.11-6^(##) 290   0.85 5.15-1^(##) 239   0.96 4.13-1^(##) 222   0.625.16-1 193   3.17 4.16-1^(##) 222   0.61 5.16-2 197   1.02 4.24-1^(##)231   0.73 5.16-3^(##) 260   0.70 4.24-24 240   3.12 5.16-4^(#) 246  2.78 4.27-1^(##) 204   0.63 5.16-5 317   4.42 4.28-1^(#) 204   3.005.16-6^(##) 217   0.35 5.1-1 244   0.85 5.16-7 458   4.75 5.1-2 315  1.02 5.33-1^(##) 233   0.69 5.2-1^(##) 258   1.07 5.38-1^(##) 316   1.165.2-2 262^($$) 0.89 5.38-2^(#) 264   4.78 5.2-3^(##) 262   0.905.39-1^(#) 260^(**) 3.58 5.2-4 333   5.32 5.40-1^(##) 251^(**) 0.785.2-5 233   0.70 5.41-1^(#) 233^(*)  4.00 5.4-1 252   0.95 5.43-1^(##)278   1.08 5.5-1 300   1.11 5.44-1 302^(**) 3.83 5.6-1 302   1.085.45-1^(#) 238   3.95 5.7-1 420   5.50 5.45-2 436   5.33 5.8-1^(##)314   1.08 5.46-1 476   5.03 5.10-1^(#) 233^(*)  4.00 5.47-2^(#) 416  0.67 Example No. without symbol: HPLC (AcOH) system; Example No. withsymbol ^(#): HPLC (TFA) system; and Example No. with symbol ^(##): UPLCsystem. In MS-ESI (m/z), ^(*): [M − H]⁻; and ^(**): [M + Na]⁺.

1. A pharmaceutical composition comprising, as an active ingredient, atleast one of a compound according to the following formula (I-b), or apharmaceutically acceptable salt thereof, or a solvate thereof; and apharmaceutically acceptable carrier:

wherein p represents an integer of 0 to 2; q represents an integer of 0to 3; Z represents N or CR⁵; R¹ each independently represents a halogenatom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkylgroup, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, aC₁₋₆ alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a—CONR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸group each independently represent a substituent selected from among ahydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, ahydroxy C₁₋₆ alkyl group, a cyanated C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₄ arylgroup, a C₇₋₂₀ aralkyl group, a heterocyclic group, a C₂₋₇ alkanoylgroup, a hydroxy C₂₋₇ alkanoyl group, a halogenated C₂₋₇ alkanoyl group,a C₃₋₈ cycloalkylcarbonyl group, a C₆₋₁₄ arylcarbonyl group, a C₇₋₂₀aralkylcarbonyl group, a heterocyclic carbonyl group, a mono-/di-C₁₋₆alkylcarbamoyl group, a mono-/di-halogenated C₁₋₆ alkylcarbamoyl group,a mono-/di-C₃₋₈ cycloalkylcarbamoyl group, a mono-/di-C₆₋₁₄arylcarbamoyl group, a mono-/di-C₇₋₂₀ aralkylcarbamoyl group, amono-/di-heterocyclic carbamoyl group, a C₁₋₆ alkylsulfonyl group, ahalogenated C₁₋₆ alkylsulfonyl group, a C₃₋₈ cycloalkylsulfonyl group, aC₆₋₁₄ arylsulfonyl group, a C₇₋₂₀ aralkylsulfonyl group, a heterocyclicsulfonyl group, a mono-/di-C₁₋₆ alkylsulfamoyl group, amono-/di-halogenated C₁₋₆ alkylsulfamoyl group, a mono-/di-C₃₋₈cycloalkylsulfamoyl group, a mono-/di-C₆₋₁₄ arylsulfamoyl group, amono-/di-C₇₋₂₀ aralkylsulfamoyl group, and a mono-/di-heterocyclicsulfamoyl group; R² represents a hydrogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆alkoxyl C₁₋₆ alkyl group; R³ each independently represents a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group,a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆alkoxyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group; R⁴ represents ahalogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸group, a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromatic heterocyclicgroup, or a 5- to 7-membered monocyclic heteroaryl group, wherein R⁷ andR⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the same definitionsas those of R⁷ and R⁸ in the above R¹, and wherein the C₃₋₈ cycloalkylgroup, the C₆₋₁₄ aryl group, the 3- to 14-membered non-aromaticheterocyclic group, and the 5- to 7-membered monocyclic heteroarylgroup, which are represented by R⁴, are each optionally substituted withone to three groups selected from among a hydroxyl group, a nitro group,a cyano group, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸group, a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromatic heterocyclicgroup, and a 5- to 7-membered monocyclic heteroaryl group, wherein R⁷and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the samedefinitions as those of R⁷ and R⁸ in the above R¹; R⁵ represents ahydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, ora C₁₋₆ alkoxyl C₁₋₆ alkyl group; and ring A′ represented by thefollowing partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group.
 2. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceuticallyacceptable carrier is selected from the group consisting of an inactivesolid diluent or filler, a sterilized aqueous solution and an organicsolvent.
 3. The pharmaceutical composition according to claim 1, whereinthe composition is present in an administration form selected from thegroup consisting of a tablet, a powder, a lozenge, a liquid, a syrup, ora suppository.
 4. The pharmaceutical composition according to claim 1,wherein the composition is formulated in a form suitable for oraladministration, buccal administration, nasal administration, parenteraladministration, transdermal administration, rectal administration,inhalation administration, or insufflation administration.
 5. A methodfor treating at least one disease or condition selected from the groupconsisting of mental disorder and condition, anxiety disorder, motordisorder, mood disorder, neurodegenerative disorder, disorder involvingdeficits in attention and/or cognition, obesity, and drug addiction,wherein the method comprises administering at least one of a compoundaccording to formula (I-b), a pharmaceutically acceptable salt thereof,or a solvate thereof, in an effective amount for treating the disease orcondition, to a subject in need of treatment of the disease orcondition:

wherein p represents an integer of 0 to 2; q represents an integer of 0to 3; Z represents N or CR⁵; R¹ each independently represents a halogenatom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆ alkylgroup, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, aC₁₋₆ alkoxylcarbonyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxylC₁₋₆ alkyl group, a C₂₋₇ alkanoyl group, a C₁₋₆ alkylthio group, a C₁₋₆alkylsulfinyl group, a C₁₋₆ alkylsulfonyl group, an —NR⁷R⁸ group, or a—CONR⁷R⁸ group wherein R⁷ and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸group each independently represent a substituent selected from among ahydrogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, ahydroxy C₁₋₆ alkyl group, a cyanated C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group, a C₆₋₁₄ arylgroup, a C₇₋₂₀ aralkyl group, a heterocyclic group, a C₂₋₇ alkanoylgroup, a hydroxy C₂₋₇ alkanoyl group, a halogenated C₂₋₇ alkanoyl group,a C₃₋₈ cycloalkylcarbonyl group, a C₆₋₁₄ arylcarbonyl group, a C₇₋₂₀aralkylcarbonyl group, a heterocyclic carbonyl group, a mono-/di-C₁₋₆alkylcarbamoyl group, a mono-/di-halogenated C₁₋₆ alkylcarbamoyl group,a mono-/di-C₃₋₈ cycloalkylcarbamoyl group, a mono-/di-C₆₋₁₄arylcarbamoyl group, a mono-/di-C₇₋₂₀ aralkylcarbamoyl group, amono-/di-heterocyclic carbamoyl group, a C₁₋₆ alkylsulfonyl group, ahalogenated C₁₋₆ alkylsulfonyl group, a C₃₋₈ cycloalkylsulfonyl group, aC₆₋₁₄ arylsulfonyl group, a C₇₋₂₀ aralkylsulfonyl group, a heterocyclicsulfonyl group, a mono-/di-C₁₋₆ alkylsulfamoyl group, amono-/di-halogenated C₁₋₆ alkylsulfamoyl group, a mono-/di-C₃₋₈cycloalkylsulfamoyl group, a mono-/di-C₆₋₁₄ arylsulfamoyl group, amono-/di-C₇₋₂₀ aralkylsulfamoyl group, and a mono-/di-heterocyclicsulfamoyl group; R² represents a hydrogen atom, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group, a hydroxy C₁₋₆ alkyl group, or a C₁₋₆alkoxyl C₁₋₆ alkyl group; R³ each independently represents a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group,a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆alkoxyl group, or a C₁₋₆ alkoxyl C₁₋₆ alkyl group; R⁴ represents ahalogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl group, a C₃₋₈cycloalkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸group, a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromatic heterocyclicgroup, or a 5- to 7-membered monocyclic heteroaryl group, wherein R⁷ andR⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the same definitionsas those of R⁷ and R⁸ in the above R¹, and wherein the C₃₋₈ cycloalkylgroup, the C₆₋₁₄ aryl group, the 3- to 14-membered non-aromaticheterocyclic group, and the 5- to 7-membered monocyclic heteroarylgroup, which are represented by R⁴, are each optionally substituted withone to three groups selected from among a hydroxyl group, a nitro group,a cyano group, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a hydroxy C₁₋₆ alkyl group, a C₁₋₆ alkoxyl group, ahalogenated C₁₋₆ alkoxyl group, a C₁₋₆ alkoxyl C₁₋₆ alkyl group, a C₁₋₆alkylthio group, a C₁₋₆ alkylsulfonyl group, a —CONR⁷R⁸ group, an —NR⁷R⁸group, a C₆₋₁₄ aryl group, a 3- to 14-membered non-aromatic heterocyclicgroup, and a 5- to 7-membered monocyclic heteroaryl group, wherein R⁷and R⁸ in the —NR⁷R⁸ group and the —CONR⁷R⁸ group have the samedefinitions as those of R⁷ and R⁸ in the above R¹; R⁵ represents ahydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a halogenated C₁₋₆alkyl group, a C₁₋₆ alkoxyl group, a halogenated C₁₋₆ alkoxyl group, ora C₁₋₆ alkoxyl C₁₋₆ alkyl group; and ring A′ represented by thefollowing partial structural formula (II′):

is selected from the group of the heteroaryls consisting of thefollowing:

and R⁶ represents a hydrogen atom, a C₁₋₆ alkyl group, a halogenatedC₁₋₆ alkyl group, or a hydroxy C₁₋₆ alkyl group.
 6. The method accordingto claim 5, wherein said at least one of a compound according to formula(I-b), a pharmaceutically acceptable salt thereof, or a solvate thereof,is administrated in an effective amount for inhibiting PDE 10, to thesubject in need of treatment of the disease or condition.
 7. Thepharmaceutical composition according to claim 1 for treating at leastone disease or condition selected from the group consisting of (1)paranoid, disorganized, catatonic, undifferentiated, or residualschizophrenia, (2) schizophreniform disorder, (3) paranoid or depressiveschizoaffective disorder, (4) paranoid disorder, (5) substance-inducedmental disorder, (6) psychosis induced by alcohol, amphetamine,cannabis, cocaine, a hallucinatory drug, an inhalant, opioid, orphencyclidine, (7) paranoic personality disorder, (8) schizotypalpersonality disorder, (9) Huntington's disease, (10) dyskinesiaassociated with dopamine agonist therapy, (11) Parkinson's disease, (12)restless legs syndrome, (13) essential tremor, (14) obsessive-compulsivedisorder, (15) Tourette's syndrome, (16) tic disorder, (17) panicdisorder, (18) agoraphobia, (19) specific phobias, (20) social phobias,(21) posttraumatic stress disorder, (22) acute stress disorder, (23)generalized anxiety disorder, (24) dementia, (25) delirium, (26)amnestic disorder, (27) mental retardation, (28) learning disorder, (29)attention-deficit hyperactivity disorder, (30) age-related cognitivedecline, (31) major depressive episode (mild level, middle level, orsevere level type), manic episode, mixed affective episode, or hypomanicepisode, (32) atypical depression, (33) melancholic depression, (34)catatonic depression, (35) postpartum mood episode, (36) postapoplecticdepression, (37) major depressive disorder, (38) dysthymicdisorder/dysthymia, (39) minor depressive disorder, (40) premenstrualdysphoric disorder, (41) postschizophrenic depressive disorder, (42)major depressive disorder occurring with mental disorder, (43) bipolardisorder, (44) cyclothymic disorder, (45) neurodegeneration associatedwith brain damage, (46) neurodegeneration associated with stroke, orneurodegeneration associated with cerebral infarction, (47)hypoglycemia-induced neurodegeneration, (48) neurodegenerationassociated with epileptic seizure, (49) neurodegeneration associatedwith neurotoxic addiction, (50) multiple system atrophy, and (51)neurodegeneration of striatal medium-sized spiny neurons.
 8. The methodaccording to claim 5, wherein the disease or condition is at least onedisease or condition selected from the group consisting of (1) paranoid,disorganized, catatonic, undifferentiated, or residual schizophrenia,(2) schizophreniform disorder, (3) paranoid or depressiveschizoaffective disorder, (4) paranoid disorder, (5) substance-inducedmental disorder, (6) psychosis induced by alcohol, amphetamine,cannabis, cocaine, a hallucinatory drug, an inhalant, opioid, orphencyclidine, (7) paranoic personality disorder, (8) schizotypalpersonality disorder, (9) Huntington's disease, (10) dyskinesiaassociated with dopamine agonist therapy, (11) Parkinson's disease, (12)restless legs syndrome, (13) essential tremor, (14) obsessive-compulsivedisorder, (15) Tourette's syndrome, (16) tic disorder, (17) panicdisorder, (18) agoraphobia, (19) specific phobias, (20) social phobias,(21) posttraumatic stress disorder, (22) acute stress disorder, (23)generalized anxiety disorder, (24) dementia, (25) delirium, (26)amnestic disorder, (27) mental retardation, (28) learning disorder, (29)attention-deficit hyperactivity disorder, (30) age-related cognitivedecline, (31) major depressive episode (mild level, middle level, orsevere level type), manic episode, mixed affective episode, or hypomanicepisode, (32) atypical depression, (33) melancholic depression, (34)catatonic depression, (35) postpartum mood episode, (36) postapoplecticdepression, (37) major depressive disorder, (38) dysthymicdisorder/dysthymia, (39) minor depressive disorder, (40) premenstrualdysphoric disorder, (41) postschizophrenic depressive disorder, (42)major depressive disorder occurring with mental disorder, (43) bipolardisorder, (44) cyclothymic disorder, (45) neurodegeneration associatedwith brain damage, (46) neurodegeneration associated with stroke, orneurodegeneration associated with cerebral infarction, (47)hypoglycemia-induced neurodegeneration, (48) neurodegenerationassociated with epileptic seizure, (49) neurodegeneration associatedwith neurotoxic addiction, (50) multiple system atrophy, and (51)neurodegeneration of striatal medium-sized spiny neurons.
 9. The methodaccording to claim 5, wherein said at least one of a compound accordingto the formula (I-b), a pharmaceutically acceptable salt thereof, or asolvate thereof is administrated in combination with one or more drugsselected from the group consisting of (1) atypical antipsychotic agents,(2) typical antipsychotic agents, (3) selective serotonin reuptakeinhibitors (SSRI), (4) selective serotonin/noradrenalin reuptakeinhibitors (SNRI), (5) selective noradrenalin/dopamine reuptakeinhibitors (NDRI), (6) noradrenergic and specific serotonergicantidepressants (NaSSA), (7) triazolopyridine antidepressants (SARI),(8) tetracyclic antidepressants, (9) tricyclic antidepressants, (10)other antidepressants, (11) α7 nicotine receptor agonists, (12) α7nicotine receptor activity modulators, (13) α7 nicotine receptor partialmodulators, (14) other PDE inhibitors, (15) NK2 antagonists, (16) NK3antagonists, (17) muscarinic M1 acetylcholine receptor activitymodulators, (18) muscarinic M2 acetylcholine receptor activitymodulators, (19) adenosine receptor modulators, (20) muscarinic M4acetylcholine receptor activity modulators, (21) muscarinic M5acetylcholine receptor activity modulators, (22) adenosine receptormodulators, (23) glycine transporter 1 (GlyT1) inhibitors, (24)glutamate enhancers, (25) NMDA receptor inhibitors, (26) metabolicglutamate receptor modulators (mGlu), (27) anti-anxiety agents, (28)sleep inducing drugs, (29) β amyloid vaccine, (30) β amyloid degradingenzyme, etc., (31) cerebral function activators, (32) cannabinoidmodulators, (33) choline esterase inhibitors, (34) MAO-B inhibitors,(35) Parkinson's disease-treating agents, (36) diabetes-treating agents,(37) antiobestic drugs, (38) hyperlipidemia-treating agents, (39)antihypertensive agents, (40) non-steroidal anti-inflammatory agents,(41) disease-modifying antirheumatic drugs (DMARDs), (42) anti-cytokineagents, (43) steroid drugs, (44) sex hormones or derivatives thereof,and (45) parathyroid hormone (PTH).